津田 真寿美 (ツダ マスミ)
医学研究院 病理系部門 病理学分野 | 准教授 |
創成研究機構化学反応創成研究拠点 | 准教授 |
Last Updated :2024/12/06
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- エクソン解析により脾辺縁帯リンパ腫と同一起源と考えられた組織球肉腫
小又 大宜, 高畑 むつみ, 牧野 吉倫, 石尾 崇, 岩崎 博, 市原 真, 津田 真寿美, 田中 伸哉, 井端 淳
臨床血液, 65, 8, 737, 741, (一社)日本血液学会-東京事務局, 2024年08月
日本語, 症例は64歳,男性。貧血を認め当科紹介となった。自己免疫性溶血性貧血の診断で治療が開始となったが,経過中に末梢血異型リンパ球が出現し腹部造影CT検査で脾腫および膵腫瘤を認めた。骨髄生検でB細胞性リンパ腫の所見を認めたため自己免疫性溶血性貧血を合併した脾辺縁帯リンパ腫と診断してbendamustineおよびrituximabの投与を開始した。貧血の改善と異型リンパ球の消失を認めていたが,膵腫瘤の増大とともに左腰背部痛が出現した。発熱と急性腎障害が出現し入院となったが入院翌日に心停止をきたし死亡した。剖検で腫瘍は膵臓を含む多数の臓器に浸潤しており,形態学的所見とCD163などの免疫組織学的検討から組織球肉腫と診断した。さらにいずれの検体もIgH遺伝子再構成が陽性で網羅的エクソン解析ではCARD11を含む共通の遺伝子異常を認め,原病の脾辺縁帯リンパ腫と組織球肉腫は同一の起源である可能性が示唆された。(著者抄録) - 脳腫瘍の分子診断と治療2 バイオマテリアルを用いたグリオーマ幹細胞ニッシェの構築
津田 真寿美, 王 磊, 小田 義崇, 種井 善一, 田中 伸哉
Brain Tumor Pathology, 41, Suppl., 101, 101, 日本脳腫瘍病理学会, 2024年05月
日本語 - Virological characteristics of the SARS-CoV-2 Omicron XBB.1.5 variant
Tamura, Tomokazu, Irie, Takashi, Deguchi, Sayaka, Yajima, Hisano, Tsuda, Masumi, Nasser, Hesham, Mizuma, Keita, Plianchaisuk, Arnon, Suzuki, Saori, Uriu, Keiya, Begum, Mst Monira, Shimizu, Ryo, Jonathan, Michael, Suzuki, Rigel, Kondo, Takashi, Ito, Hayato, Kamiyama, Akifumi, Yoshimatsu, Kumiko, Shofa, Maya, Hashimoto, Rina, Anraku, Yuki, Kimura, Kanako Terakado, Kita, Shunsuke, Sasaki, Jiei, Sasaki-Tabata, Kaori, Maenaka, Katsumi, Nao, Naganori, Wang, Lei, Oda, Yoshitaka, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ikeda, Terumasa, Saito, Akatsuki, Matsuno, Keita, Ito, Jumpei, Tanaka, Shinya, Sato, Kei, Hashiguchi, Takao, Takayama, Kazuo, Fukuhara, Takasuke
Nature Communications, 15, 2024年02月08日
英語, 研究論文(学術雑誌), Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the S486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determine the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. We provide the intrinsic pathogenicity of XBB.1 and XBB.1.5 in hamsters. Importantly, we find that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC suppression. In vivo experiments using recombinant viruses reveal that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, our study identifies the two viral functions defined the difference between XBB.1 and XBB.1.5.
Combining expertise to characterize the SARS-CoV-2 Omicron XBB.1.5 variant. 京都大学プレスリリース. 2024-02-19. - Virological characteristics of the SARS-CoV-2 Omicron XBB.1.5 variant.
Tomokazu Tamura, Takashi Irie, Sayaka Deguchi, Hisano Yajima, Masumi Tsuda, Hesham Nasser, Keita Mizuma, Arnon Plianchaisuk, Saori Suzuki, Keiya Uriu, Mst Monira Begum, Ryo Shimizu, Michael Jonathan, Rigel Suzuki, Takashi Kondo, Hayato Ito, Akifumi Kamiyama, Kumiko Yoshimatsu, Maya Shofa, Rina Hashimoto, Yuki Anraku, Kanako Terakado Kimura, Shunsuke Kita, Jiei Sasaki, Kaori Sasaki-Tabata, Katsumi Maenaka, Naganori Nao, Lei Wang, Yoshitaka Oda, Terumasa Ikeda, Akatsuki Saito, Keita Matsuno, Jumpei Ito, Shinya Tanaka, Kei Sato, Takao Hashiguchi, Kazuo Takayama, Takasuke Fukuhara
Nature communications, 15, 1, 1176, 1176, 2024年02月08日, [国際誌]
英語, 研究論文(学術雑誌), Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the S486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determine the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. We provide the intrinsic pathogenicity of XBB.1 and XBB.1.5 in hamsters. Importantly, we find that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC suppression. In vivo experiments using recombinant viruses reveal that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, our study identifies the two viral functions defined the difference between XBB.1 and XBB.1.5. - ハムスター肺炎モデルを用いたSARS-CoV-2肺炎の病理組織学的解析(Histopathological analysis of hamster SARS-CoV-2 pneumonia model)
小田 義崇, 津田 真寿美, 王 磊, 種井 善一, 福原 崇介, 佐藤 佳, 田中 伸哉
日本病理学会会誌, 113, 1, 301, 301, (一社)日本病理学会, 2024年02月
英語 - 神経性食指不振症の病理解剖症例(Autopsy case report of anorexia nervosa)
白井 裕介, 種井 善一, 川内 真, 松居 剛志, 小田 義崇, 津田 真寿美, 篠原 敏也, 太田 聡, 田中 伸哉
日本病理学会会誌, 113, 1, 344, 344, (一社)日本病理学会, 2024年02月
英語 - 正中弓状靱帯症候群と膵頭部癌により致死的な十二指腸出血を来たした1剖検例(An autopsy case of fatal hemorrhage due to median arch ligament syndrome and pancreatic cancer)
伊勢 昂生, 大塚 拓也, 濱 憲輝, 潟沼 朗生, 小田 義崇, 種井 善一, 津田 真寿美, 太田 聡, 篠原 敏也, 田中 伸哉
日本病理学会会誌, 113, 1, 398, 399, (一社)日本病理学会, 2024年02月
英語 - 脊髄capillary hemangiomaの病理像(Pathology of the capillary hemangioma of the spinal cord)
種井 善一, 小野 裕介, 小田 義崇, 津田 真寿美, 大竹 安史, 今村 博幸, 小柳 泉, 飛騨 一利, 水上 裕輔, 田中 伸哉
日本病理学会会誌, 113, 1, 436, 436, (一社)日本病理学会, 2024年02月
英語 - マントルリンパ腫とびまん性大細胞型B細胞性リンパ腫のdiscordant lymphomaの一解剖例(An autopsy case of discordant lymphoma: mantle cell lymphoma and diffuse large B-cell lymphoma)
岸浪 建, 小田 義崇, 王 磊, 江端 浩, 加藤 万里絵, 種井 善一, 津田 真寿美, 宮城島 拓人, 田中 伸哉
日本病理学会会誌, 113, 1, 453, 453, (一社)日本病理学会, 2024年02月
英語 - 慢性肺血栓塞栓症の二剖検例
岸本 佳子, 種井 善一, 青木 健志, 棒田 浩基, 小田 義崇, 王 磊, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 113, 1, 468, 468, (一社)日本病理学会, 2024年02月
日本語 - 14年後に再発したBRAF V600E変異を有するlow-grade gliomaの1例
黒田 花音, 小田 義崇, 岡本 迪成, 村木 岳史, 種井 善一, 王 磊, 津田 真寿美, 高阪 真路, 西原 広史, 田中 伸哉
日本病理学会会誌, 113, 1, 482, 482, (一社)日本病理学会, 2024年02月
日本語 - 左同名半盲をきたした頭蓋内腫瘍の一例
長野 七海, 種井 善一, 福島 大地, 小田 義崇, 王 磊, 津田 真寿美, 山村 明範, 田中 伸哉
日本病理学会会誌, 113, 1, 482, 482, (一社)日本病理学会, 2024年02月
日本語 - BRAF p.V600E変異を有するHigh-grade Gliomaの病理学的研究
京野 里虹, 種井 善一, 伊師 雪友, 小田 義崇, 王 磊, 津田 真寿美, 佐藤 憲市, 寺坂 俊介, 田中 伸哉
日本病理学会会誌, 113, 1, 482, 482, (一社)日本病理学会, 2024年02月
日本語 - MELAS様症状とMT-ATP6 m.8639T>C変異を伴う71歳男性の一剖検例
戸田 壮太郎, 小田 義崇, 種井 善一, 王 磊, 大森 優子, 石田 雄介, 津田 真寿美, 松岡 健, 田中 伸哉
日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
日本語 - 30代男性のアミロイドアンギオパチーの病理像
馬詰 知佐, 種井 善一, 小田 義崇, 藤井 恭子, 王 磊, 津田 真寿美, 山口 大志, 中村 博彦, 田中 伸哉
日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
日本語 - FFPE検体の質量分析による交感神経節のレビー小体関連分子の探索
宮本 裕也, 種井 善一, 小田 義崇, 王 磊, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
日本語 - Nerve sheath myxomaのプロテオミクス解析による免疫組織化学マーカー探索
鍵谷 豪太, 種井 善一, 小田 義崇, 王 磊, 津田 真寿美, 飛騨 一利, 田中 伸哉
日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
日本語 - Structure-changeable luminescent Eu(III) complex as a human cancer grade probing system for brain tumor diagnosis
Mengfei Wang, Masaya Kono, Yusaku Yamaguchi, Jahidul Islam, Sunao Shoji, Yuichi Kitagawa, Koji Fushimi, Sora Watanabe, Go Matsuba, Akihisa Yamamoto, Motomu Tanaka, Masumi Tsuda, Shinya Tanaka, Yasuchika Hasegawa
Scientific Reports, 14, 1, Springer Science and Business Media LLC, 2024年01月22日
研究論文(学術雑誌), Abstract
Accurate determination of human tumor malignancy is important for choosing efficient and safe therapies. Bioimaging technologies based on luminescent molecules are widely used to localize and distinguish active tumor cells. Here, we report a human cancer grade probing system (GPS) using a water-soluble and structure-changeable Eu(III) complex for the continuous detection of early human brain tumors of different malignancy grades. Time-dependent emission spectra of the Eu(III) complexes in various types of tumor cells were recorded. The radiative rate constants (kr), which depend on the geometry of the Eu(III) complex, were calculated from the emission spectra. The tendency of the kr values to vary depended on the tumor cells at different malignancy grades. Between T = 0 and T = 3 h of invasion, the kr values exhibited an increase of 4% in NHA/TS (benign grade II gliomas), 7% in NHA/TSR (malignant grade III gliomas), and 27% in NHA/TSRA (malignant grade IV gliomas). Tumor cells with high-grade malignancy exhibited a rapid upward trend in kr values. The cancer GPS employs Eu(III) emissions to provide a new diagnostic method for determining human brain tumor malignancy. - SARS-CoV-2オミクロン株におけるハムスター肺炎モデルの病理組織学的解析
小田 義崇, 津田 真寿美, 王 磊, 種井 善一, 福原 崇介, 佐藤 佳, 田中 伸哉
日本病理学会会誌, 112, 2, 132, 132, (一社)日本病理学会, 2023年10月
日本語 - A Case of Uterine Tumor Resembling Ovarian Sex Cord Tumor With Prominent Myxoid Features.
Koki Ise, Zen-Ichi Tanei, Yoshitaka Oda, Satoshi Tanikawa, Hirokazu Sugino, Yusuke Ishida, Masumi Tsuda, Yuko Gotoda, Kunihiko Nishiwaki, Hiroyuki Yanai, Tadashi Hasegawa, Kazuo Nagashima, Shinya Tanaka
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists, 2023年06月14日, [国際誌]
英語, 研究論文(学術雑誌), Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor with low malignant potential that commonly occurs in middle age. Although more than 100 cases have been reported to date, myxoid morphology is not well documented. Here, we present a 75-yr-old woman with abnormal vaginal bleeding, with an 8-cm mass in the uterine corpus detected by irregular, high-intensity signaling on T2-weighted imaging. The uterine mass had a glistening mucinous appearance on gross examination. Microscopically, most of the tumor cells were floating in the myxoid stroma. The tumor cells formed clusters or nests with abundant cytoplasm, while some exhibited trabecular or rhabdoid appearances. Immunohistochemically, tumor cells were positive for pancytokeratin (AE1/AE3), α-smooth muscle actin, CD10, progesterone receptor, and some sex cord markers such as calretinin, inhibin, CD56, steroidogenic factor-1. Electron microscopy demonstrated epithelial and sex cord differentiation. This tumor was negative for JAZF1-JJAZ1 fusion gene that is frequently found in low-grade endometrial stromal sarcoma. Fusion genes related to UTROSCT, including NCOA2/3, were not detected by reverse transcription polymerase chain reaction. The present case suggests that UTROSCT should be included in the differential diagnosis of myxoid uterine tumors. - てんかんを発症した72歳女性の右側頭葉内側部病変
種井 善一, 浅野目 卓, 小野 裕介, 小田 義崇, 王 磊, 津田 真寿美, 佐藤 憲市, 水上 裕輔, 田中 伸哉
Brain Tumor Pathology, 40, Suppl., 126, 126, 日本脳腫瘍病理学会, 2023年05月
日本語 - 拡張型心筋症を発症したEmery-Dreifuss型筋ジストロフィーの一剖検例
佐々木 美羽, 種井 善一, 松島 理明, 石垣 隆弘, 桑原 健, 小田 義嵩, 谷川 聖, 津田 真寿美, 矢部 一郎, 田中 伸哉
日本病理学会会誌, 112, 1, 381, 381, (一社)日本病理学会, 2023年03月
日本語 - 脳腫瘍に対する病理研究者としての克服戦略 ハイドロゲルによる髄膜腫幹細胞の探索(Strategies for overcoming the brain tumors presented by pathology researchers Search for meningioma stem cells using hydrogel)
小田 義崇, 津田 真寿美, 湯澤 明夏, 王 磊, 鈴鹿 淳, ハビバ・ウンマ, 種井 善一, モーウリン・クリスチアン, グン 剣萍, 田中 伸哉
日本病理学会会誌, 112, 1, 184, 184, (一社)日本病理学会, 2023年03月
英語 - TKIs耐性膠芽腫細胞の特性と耐性メカニズムの解析
津田 真寿美, 王 磊, 小田 義崇, 谷川 聖, 種井 善一, 田中 伸哉
日本病理学会会誌, 112, 1, 278, 278, (一社)日本病理学会, 2023年03月
日本語 - ハイドロゲルを用いた中皮腫幹細胞の創出および治療標的分子の探索
加藤 万里絵, 杉野 弘和, 津田 真寿美, 王 磊, 種井 善一, 小田 義崇, 谷川 聖, グン 剣萍, 田中 伸哉
日本病理学会会誌, 112, 1, 332, 332, (一社)日本病理学会, 2023年03月
日本語 - 72歳女性のMultinodular and Vacuolating Neuronal Tumor of the cerebrumの1例
寺島 祐樹, 種井 善一, 浅野目 卓, 黒田 花音, 小田 義崇, 谷川 聖, 王 磊, 津田 真寿美, 佐藤 憲市, 田中 伸哉
日本病理学会会誌, 112, 1, 375, 375, (一社)日本病理学会, 2023年03月
日本語 - JCVとCMVの脳幹部重複感染症例におけるウイルスの局在解析
黒田 花音, 種井 善一, 岡崎 ななせ, 工藤 彰彦, 阿部 恵, 寺島 祐樹, 谷川 聖, 津田 真寿美, 矢部 一郎, 田中 伸哉
日本病理学会会誌, 112, 1, 375, 375, (一社)日本病理学会, 2023年03月
日本語 - 慢性血栓塞栓性肺高血圧症の一剖検例
岸本 佳子, 種井 善一, 青木 健志, 加藤 万里絵, 小田 義崇, 谷川 聖, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 112, 1, 378, 378, (一社)日本病理学会, 2023年03月
日本語 - Becker型筋ジストロフィーの兄弟剖検症例の病理組織学的検討
宮本 裕也, 種井 善一, 谷川 聖, 小田 義崇, 津田 真寿美, 加納 崇裕, 横田 卓, 矢部 一郎, 田中 伸哉
日本病理学会会誌, 112, 1, 378, 378, (一社)日本病理学会, 2023年03月
日本語 - 電子顕微鏡的検討を行ったラブドイド髄膜腫の一症例
戸田 壮太郎, 種井 善一, 京野 里虹, 寺島 祐樹, 谷川 聖, 小田 義崇, 王 磊, 津田 真寿美, 瀬尾 善宣, 田中 伸哉
日本病理学会会誌, 112, 1, 380, 380, (一社)日本病理学会, 2023年03月
日本語 - 髄膜腫の骨化におけるEpithelial-mesenchymal transitionの関与についての検討
京野 里虹, 種井 善一, 寺島 祐樹, 小田 義崇, 谷川 聖, 王 磊, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 112, 1, 381, 381, (一社)日本病理学会, 2023年03月
日本語 - FFPE検体の質量分析による肺小細胞癌の脳転移関連分子の解析
江端 美織, 何 錦涛, 小田 義崇, 谷川 聖, 王 磊, 津田 真寿美, 種井 善一, 田中 伸哉
日本病理学会会誌, 112, 1, 383, 383, (一社)日本病理学会, 2023年03月
日本語 - 進行性核上性麻痺にTDP43 pathologyを合併した一剖検例
鍵谷 豪太, 種井 善一, 谷川 聖, 小田 義崇, 王 磊, 津田 真寿美, 大槻 美佳, 田中 伸哉
日本病理学会会誌, 112, 1, 379, 379, (一社)日本病理学会, 2023年03月
日本語 - 拡張型心筋症を発症したEmery-Dreifuss型筋ジストロフィーの一剖検例
佐々木 美羽, 種井 善一, 松島 理明, 石垣 隆弘, 桑原 健, 小田 義嵩, 谷川 聖, 津田 真寿美, 矢部 一郎, 田中 伸哉
日本病理学会会誌, 112, 1, 381, 381, (一社)日本病理学会, 2023年03月
日本語 - Geometrical analysis identified morphological features of hydrogel-induced cancer stem cells in synovial sarcoma model cells
Zannatul Ferdous, Jean-Emmanuel Clément, Jian Ping Gong, Shinya Tanaka, Tamiki Komatsuzaki, Masumi Tsuda
Biochemical and Biophysical Research Communications, 642, 41, 49, Elsevier BV, 2023年01月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Cancer stem cells (CSCs) has been a key target to cure cancer patients completely. Although many CSC markers have been identified, they are frequently cancer type-specific and those expressions are occasionally variable, which becomes an obstacle to elucidate the characteristics of the CSCs. Here we scrutinized the relationship between stemness elevation and geometrical features of single cells. The PAMPS hydrogel was utilized to create the CSCs from mouse myoblast C2C12 and its synovial sarcoma model cells. qRT-PCR analysis confirmed the significant increase in expression levels of Sox2, Nanog, and Oct3/4 on the PAMPS gel, which was higher in the synovial sarcoma model cells. Of note, the morphological heterogeneity was appeared on the PAMPS gel, mainly including flat spreading, elongated spindle, and small round cells, and the Sox2 expression was highest in the small round cells. To examine the role of morphological differences in the elevation of stemness, over 6,400 cells were segmented along with the Sox2 intensity, and 12 geometrical features were extracted at single cell level. A nonlinear mapping of the geometrical features by using uniform manifold approximation and projection (UMAP) clearly revealed the existence of relationship between morphological differences and the stemness elevation, especially for C2C12 and its synovial sarcoma model on the PAMPS gel in which the small round cells possess relatively high Sox2 expression on the PAMPS gel, which supports the strong relationship between morphological changes and the stemness elevation. Taken together, these geometrical features can be useful for morphological profiling of CSCs to classify and distinguish them for understanding of their role in disease progression and drug discovery. - Monitoring fusion kinetics of viral and target cell membranes in living cells using a SARS-CoV-2 spike-protein-mediated membrane fusion assay
Hesham Nasser, Ryo Shimizu, Jumpei Ito, Akatsuki Saito, Kei Sato, Terumasa Ikeda, Keita Matsuno, Naganori Nao, Hirofumi Sawa, Mai Kishimoto, Shinya Tanaka, Masumi Tsuda, Lei Wang, Yoshikata Oda, Marie Kato, Zannatul Ferdous, Hiromi Mouri, Kenji Shishido, Takasuke Fukuhara, Tomokazu Tamura, Rigel Suzuki, Hayato Ito, Daichi Yamasoba, Izumi Kimura, Naoko Misawa, Keiya Uriu, Yusuke Kosugi, Shigeru Fujita, Mai Suganami, Mika Chiba, Ryo Yoshimura, So Nakagawa, Jiaqi Wu, Akifumi Takaori-Kondo, Kotaro Shirakawa, Kayoko Nagata, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Yusuke Tashiro, Yugo Kawai, Takashi Irie, Ryoko Kawabata, MST Monira Begum, Otowa Takahashi, Kimiko Ichihara, Takamasa Ueno, Chihiro Motozono, Mako Toyoda, Yuri L. Tanaka, Erika P. Butlertanaka, Maya Shofa, Kazuo Takayama, Rina Hashimoto, Sayaka Deguchi, Takao Hashiguchi, Tateki Suzuki, Kanako Kimura, Jiei Sasaki, Yukari Nakajima, Kaori Tabata
STAR Protocols, 3, 4, 101773, 101773, Elsevier BV, 2022年12月
研究論文(学術雑誌) - Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant.
Akatsuki Saito, Tomokazu Tamura, Jiri Zahradnik, Sayaka Deguchi, Koshiro Tabata, Yuki Anraku, Izumi Kimura, Jumpei Ito, Daichi Yamasoba, Hesham Nasser, Mako Toyoda, Kayoko Nagata, Keiya Uriu, Yusuke Kosugi, Shigeru Fujita, Maya Shofa, Mst Monira Begum, Ryo Shimizu, Yoshitaka Oda, Rigel Suzuki, Hayato Ito, Naganori Nao, Lei Wang, Masumi Tsuda, Kumiko Yoshimatsu, Jin Kuramochi, Shunsuke Kita, Kaori Sasaki-Tabata, Hideo Fukuhara, Katsumi Maenaka, Yuki Yamamoto, Tetsuharu Nagamoto, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Takamasa Ueno, Gideon Schreiber, Akifumi Takaori-Kondo, Kotaro Shirakawa, Hirofumi Sawa, Takashi Irie, Takao Hashiguchi, Kazuo Takayama, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, Kei Sato
Cell host & microbe, 30, 11, 1540, 1555, 2022年11月09日, [国際誌]
英語, 研究論文(学術雑誌), The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5. - Force-triggered rapid microstructure growth on hydrogel surface for on-demand functions
Qifeng Mu, Kunpeng Cui, Zhi Jian Wang, Takahiro Matsuda, Wei Cui, Hinako Kato, Shotaro Namiki, Tomoko Yamazaki, Martin Frauenlob, Takayuki Nonoyama, Masumi Tsuda, Shinya Tanaka, Tasuku Nakajima, Jian Ping Gong
Nature Communications, 13, 1, Springer Science and Business Media LLC, 2022年10月20日
研究論文(学術雑誌), Abstract
Living organisms share the ability to grow various microstructures on their surface to achieve functions. Here we present a force stamp method to grow microstructures on the surface of hydrogels based on a force-triggered polymerisation mechanism of double-network hydrogels. This method allows fast spatial modulation of the morphology and chemistry of the hydrogel surface within seconds for on-demand functions. We demonstrate the oriented growth of cells and directional transportation of water droplets on the engineered hydrogel surfaces. This force-triggered method to chemically engineer the hydrogel surfaces provides a new tool in addition to the conventional methods using light or heat, and will promote the wide application of hydrogels in various fields. - SARS-CoV-2変異株を用いたハムスター肺炎モデルの病理組織学的解析
小田 義崇, 津田 真寿美, 王 磊, 谷川 聖, 種井 善一, 佐藤 佳, 福原 崇介, 田中 伸哉
日本病理学会会誌, 111, 2, 113, 113, (一社)日本病理学会, 2022年10月
日本語 - ハイドロゲルを用いた髄膜腫がん幹細胞マーカーの検索(Identification of novel stemness marker of meningioma by using hydrogel)
小田 義崇, 津田 真寿美, 湯澤 明夏, 王 磊, 谷川 聖, 種井 善一, グン 剣萍, 田中 伸哉
日本癌学会総会記事, 81回, P, 2111, (一社)日本癌学会, 2022年09月
英語 - Evaluation of the context of downstream N- and free N-glycomic alterations induced by swainsonine in HepG2 cells.
Chie Morikawa, Kanako Sugiura, Keina Kondo, Yurie Yamamoto, Yuma Kojima, Yurika Ozawa, Hiroki Yoshioka, Nobuaki Miura, Jinhua Piao, Kazue Okada, Hisatoshi Hanamatsu, Masumi Tsuda, Shinya Tanaka, Jun-Ichi Furukawa, Yasuro Shinohara
Biochimica et biophysica acta. General subjects, 1866, 9, 130168, 130168, 2022年05月17日, [国際誌]
英語, 研究論文(学術雑誌), Swainsonine (SWA), a potent inhibitor of class II α-mannosidases, is present in a number of plant species worldwide and causes severe toxicosis in livestock grazing these plants. The mechanisms underlying SWA-induced animal poisoning are not fully understood. In this study, we analyzed the alterations that occur in N- and free N-glycomic upon addition of SWA to HepG2 cells to understand better SWA-induced glycomic alterations. After SWA addition, we observed the appearance of SWA-specific glycomic alterations, such as unique fucosylated hybrid-type and fucosylated M5 (M5F) N-glycans, and a remarkable increase in all classes of Gn1 FNGs. Further analysis of the context of these glycomic alterations showed that (fucosylated) hybrid type N-glycans were not the precursors of these Gn1 FNGs and vice versa. Time course analysis revealed the dynamic nature of glycomic alterations upon exposure of SWA and suggested that accumulation of free N-glycans occurred earlier than that of hybrid-type N-glycans. Hybrid-type N-glycans, of which most were uniquely core fucosylated, tended to increase slowly over time, as was observed for M5F N-glycans. Inhibition of swainsonine-induced unique fucosylation of hybrid N-glycans and M5 by coaddition of 2-fluorofucose caused significant increases in paucimannose- and fucosylated paucimannose-type N-glycans, as well as paucimannose-type free N-glycans. The results not only revealed the gross glycomic alterations in HepG2 cells induced by swainsonine, but also provide information on the global interrelationships between glycomic alterations. - Psammomatous meningioma周囲に脳実質石灰化を認めた一例
岡崎 ななせ, 谷川 聖, 種井 善一, 津田 真寿美, 大澤 崇宏, 松野 吉宏, 田中 伸哉
Brain Tumor Pathology, 39, Suppl., 124, 124, 日本脳腫瘍病理学会, 2022年05月
日本語 - Psammomatous meningioma周囲に脳実質石灰化を認めた一例
岡崎 ななせ, 谷川 聖, 種井 善一, 津田 真寿美, 大澤 崇宏, 松野 吉宏, 田中 伸哉
Brain Tumor Pathology, 39, Suppl., 124, 124, 日本脳腫瘍病理学会, 2022年05月
日本語 - 細胞外基質の電位変化に伴うJCウイルス増殖の制御
谷川 聖, 野々山 貴行, 津田 真寿美, 王 磊, 種井 善一, Gong Jian Ping, 田中 伸哉
日本病理学会会誌, 111, 1, 263, 263, (一社)日本病理学会, 2022年03月
日本語 - 脊髄capillary hemangiomaの病理像
種井 善一, 津田 真寿美, 小田 義崇, 谷川 聖, 杉野 弘和, 大竹 安史, 今村 博幸, 小柳 泉, 飛騨 一利, 田中 伸哉
日本病理学会会誌, 111, 1, 264, 264, (一社)日本病理学会, 2022年03月
日本語 - びまん性大細胞型B細胞性リンパ腫の化学療法中に突然死した1剖検例
加藤 万里絵, 種井 善一, 小島 圭祐, 太田 秀一, ウンマ・ハビバ, 小田 義崇, 谷川 聖, 杉野 弘和, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 111, 1, 308, 308, (一社)日本病理学会, 2022年03月
日本語 - 内頸動脈瘤術後に急激な意識障害をきたした神経線維腫症1型の一剖検例
京野 里虹, 種井 善一, 岡崎 ななせ, 長内 俊也, 小田 義崇, 谷川 聖, 杉野 弘和, 津田 真寿美, 藤村 幹, 田中 伸哉
日本病理学会会誌, 111, 1, 356, 356, (一社)日本病理学会, 2022年03月
日本語 - 細胞外基質の電位変化に伴うJCウイルス増殖の制御
谷川 聖, 野々山 貴行, 津田 真寿美, 王 磊, 種井 善一, Gong Jian Ping, 田中 伸哉
日本病理学会会誌, 111, 1, 263, 263, (一社)日本病理学会, 2022年03月
日本語 - 脊髄capillary hemangiomaの病理像
種井 善一, 津田 真寿美, 小田 義崇, 谷川 聖, 杉野 弘和, 大竹 安史, 今村 博幸, 小柳 泉, 飛騨 一利, 田中 伸哉
日本病理学会会誌, 111, 1, 264, 264, (一社)日本病理学会, 2022年03月
日本語 - びまん性大細胞型B細胞性リンパ腫の化学療法中に突然死した1剖検例
加藤 万里絵, 種井 善一, 小島 圭祐, 太田 秀一, ウンマ・ハビバ, 小田 義崇, 谷川 聖, 杉野 弘和, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 111, 1, 308, 308, (一社)日本病理学会, 2022年03月
日本語 - 内頸動脈瘤術後に急激な意識障害をきたした神経線維腫症1型の一剖検例
京野 里虹, 種井 善一, 岡崎 ななせ, 長内 俊也, 小田 義崇, 谷川 聖, 杉野 弘和, 津田 真寿美, 藤村 幹, 田中 伸哉
日本病理学会会誌, 111, 1, 356, 356, (一社)日本病理学会, 2022年03月
日本語 - Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.
Rigel Suzuki, Daichi Yamasoba, Izumi Kimura, Lei Wang, Mai Kishimoto, Jumpei Ito, Yuhei Morioka, Naganori Nao, Hesham Nasser, Keiya Uriu, Yusuke Kosugi, Masumi Tsuda, Yasuko Orba, Michihito Sasaki, Ryo Shimizu, Ryoko Kawabata, Kumiko Yoshimatsu, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Hirofumi Sawa, Terumasa Ikeda, Takashi Irie, Keita Matsuno, Shinya Tanaka, Takasuke Fukuhara, Kei Sato
Nature, 603, 7902, 700, 705, 2022年03月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern1. In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell-cell fusion2,3, the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity. - Engineering of an electrically charged hydrogel implanted into a traumatic brain injury model for stepwise neuronal tissue reconstruction
Satoshi Tanikawa, Yuki Ebisu, Tomáš Sedlačík, Shingo Semba, Takayuki Nonoyama, Akira Hirota, Taiga Takahashi, Kazushi Yamaguchi, Masamichi Imajo, Hinako Kato, Takuya Nishimura, Zen-ichi Tanei, Masumi Tsuda, Tomomi Nemoto, Jian Ping Gong, Shinya Tanaka
Cold Spring Harbor Laboratory, 2022年02月19日
Abstract
Neural regeneration is extremely difficult to achieve. In traumatic brain injuries, the loss of brain parenchyma volume hinders neural regeneration. In this study, neuronal tissue engineering was performed by using electrically charged hydrogels composed of cationic and anionic monomers in a 1:1 ratio (C1A1 hydrogel), which served as an effective scaffold for the attachment of neural stem cells (NSCs). In the 3D environment of porous C1A1 hydrogels engineered by the cryogelation technique, NSCs differentiated into neuroglial cells. The C1A1 porous hydrogel was implanted into brain defects in a mouse traumatic damage model. The VEGF-immersed C1A1 porous hydrogel promoted host-derived vascular network formation together with the infiltration of macrophages/microglia and astrocytes into the gel. Furthermore, the stepwise transplantation of GFP-labeled NSCs supported differentiation to glial and neuronal cells. Therefore, this two-step method for neural regeneration may become a new approach for therapeutic brain tissue reconstruction after brain damage in the future.
One Sentence Summary
Brain tissue reconstruction using charged hydrogel and stepwise NCS injection - Novel rapid immunohistochemistry using an alternating current electric field identifies Rac and Cdc42 activation in human colon cancer FFPE tissues.
Masumi Tsuda, Runa Horio, Lei Wang, Tomoko Takenami, Jun Moriya, Jun Suzuka, Hirokazu Sugino, Zenichi Tanei, Mishie Tanino, Shinya Tanaka
Scientific reports, 12, 1, 1733, 1733, 2022年02月02日, [国際誌]
英語, 研究論文(学術雑誌), It is important to determine the activation status of Rac and Cdc42 in cancer tissues for the prediction of metastasis and patient prognosis. However, it has been impossible to detect their spatial activation on formalin-fixed paraffin embedded (FFPE) surgical specimens thus far. Here, we established a novel detection technique for activated Rac/Cdc42 in human colon cancer FFPE tissues by using a p21-activated kinase (PAK)-Rac binding domain (RBD) detection probe fused with glutathione S-transferase (GST), designated GST-PAK-RBD, and novel rapid-immunohistochemistry (R-IHC) systems using noncontact alterating-current electric field mixing, although there is a technical limitation in that it may not distinguish between Rac members and Cdc42. In 50 cases of colon cancer, various activation patterns of Rac/Cdc42 were observed, which were designated plasma membrane, cytoplasm, mixed pattern, and polarized distribution. The activity was striking in the invasive fronts of tumors and significantly correlated with tumor invasion properties evaluated by TNM classification. Of note, in tissue microarray (TMA) samples, 29 of 33 cases demonstrated higher Rac1/Cdc42 activity in the tumor area than the corresponding normal mucosa. In addition, positive correlations were detected between Rac/Cdc42 activity and clinicopathological factors such as venous and lymphatic vessel invasion. These results suggest that understanding Rac and Cdc42 activations in cancer tissues would be valuable as an option for molecular therapy as personalized medicine. - Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer.
Masumi Tsuda, Misa Noguchi, Tsuyoshi Kurai, Yuji Ichihashi, Koki Ise, Lei Wang, Yusuke Ishida, Mishie Tanino, Satoshi Hirano, Masahiro Asaka, Shinya Tanaka
Cancer science, 112, 12, 5100, 5113, 2021年12月, [国際誌]
英語, 研究論文(学術雑誌), In 2020, the worldwide incidence and mortality of colorectal cancer (CRC) were third and second, respectively. As the 5-y survival rate is low when CRC is diagnosed at an advanced stage, a reliable method to predict CRC susceptibility is important for preventing the onset and development and improving the prognosis of CRC. Therefore, we focused on the normal colonic mucosa to investigate changes in gene expression that may induce subsequent genetic alterations that induce malignant transformation. Comprehensive gene expression profiling in the normal mucosa adjacent to colon cancer (CC) compared with tissue from non-colon cancer patients was performed. PCR arrays and qRT-PCR revealed that the expression of 5 genes involved in the immune response, including MYD88, was increased in the normal mucosa of CC patients. The expression levels of MYD88 were strikingly increased in precancerous normal mucosa specimens, which harbored no somatic mutations, as shown by immunohistochemistry. Microarray analysis identified 2 novel RNA-controlling molecules, EXOSC3 and CNOT4, that were significantly upregulated in the normal mucosa of CC patients and were clearly visualized in the nuclei. Forced expression of EXOSC3 and CNOT4 in human colonic epithelial cells increased the expression of IFNGR1, MYD88, NFκBIA, and STAT3 and activated ERK1/2 and JNK in 293T cells. Taken together, these results suggested that, in the inflamed mucosa, EXOSC3- and CNOT4-mediated RNA stabilization, including that of MYD88, may trigger the development of cancer and can serve as a potential predictive marker and innovative treatment to control cancer development. - Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation.
Akatsuki Saito, Takashi Irie, Rigel Suzuki, Tadashi Maemura, Hesham Nasser, Keiya Uriu, Yusuke Kosugi, Kotaro Shirakawa, Kenji Sadamasu, Izumi Kimura, Jumpei Ito, Jiaqi Wu, Kiyoko Iwatsuki-Horimoto, Mutsumi Ito, Seiya Yamayoshi, Samantha Loeber, Masumi Tsuda, Lei Wang, Seiya Ozono, Erika P Butlertanaka, Yuri L Tanaka, Ryo Shimizu, Kenta Shimizu, Kumiko Yoshimatsu, Ryoko Kawabata, Takemasa Sakaguchi, Kenzo Tokunaga, Isao Yoshida, Hiroyuki Asakura, Mami Nagashima, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Kazuhisa Yoshimura, Akifumi Takaori-Kondo, Masaki Imai, Shinya Tanaka, So Nakagawa, Terumasa Ikeda, Takasuke Fukuhara, Yoshihiro Kawaoka, Kei Sato
Nature, 602, 7896, 300, 306, 2021年11月25日, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), During the current SARS-CoV-2 pandemic, a variety of mutations have accumulated in the viral genome, and currently, four variants of concern (VOCs) are considered potentially hazardous to human society1. The recently emerged B.1.617.2/Delta VOC is closely associated with the COVID-19 surge that occurred in India in the spring of 20212. However, its virological properties remain unclear. Here, we show that the B.1.617.2/Delta variant is highly fusogenic and notably more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates spike protein cleavage and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity than its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity. - Hydroxyapatite‐hybridized double‐network hydrogel surface enhances differentiation of bone marrow‐derived mesenchymal stem cells to osteogenic cells
Takuma Kaibara, Lei Wang, Masumi Tsuda, Takayuki Nonoyama, Takayuki Kurokawa, Norimasa Iwasaki, Jian Ping Gong, Shinya Tanaka, Kazunori Yasuda
Journal of Biomedical Materials Research Part A, Wiley, 2021年10月28日
研究論文(学術雑誌) - ハイドロゲルを用いた新規髄膜腫治療標的分子の検討(Analysis of novel therapeutic target for meningioma using hydrogel)
小田 義崇, 津田 真寿美, 湯澤 明夏, 王 磊, Umma Habiba, 杉野 弘和, 種井 善一, グン 剣萍, 田中 伸哉
日本病理学会会誌, 110, 2, 110, 110, (一社)日本病理学会, 2021年10月
英語 - ハイドロキシアパタイト複合化ダブルネットワークゲル上での骨髄間葉系幹細胞の骨分化能評価
甲斐原 拓真, 王 磊, 津田 真寿美, 野々山 貴行, 黒川 孝幸, きょう 剣萍, 岩崎 倫政, 田中 伸哉, 安田 和則
日本整形外科学会雑誌, 95, 8, S1561, S1561, (公社)日本整形外科学会, 2021年08月
日本語 - Comprehensive molecular profiling of pulmonary pleomorphic carcinoma.
Masaaki Nagano, Shinji Kohsaka, Takuo Hayashi, Toshihide Ueno, Shinya Kojima, Aya Shinozaki-Ushiku, Shigeki Morita, Masumi Tsuda, Shinya Tanaka, Toshiya Shinohara, Yuko Omori, Fumiko Sugaya, Hiroaki Kato, Yoshiaki Narita, Jun Nakajima, Kenji Suzuki, Kazuya Takamochi, Hiroyuki Mano
NPJ precision oncology, 5, 1, 57, 57, 2021年06月22日, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Information regarding the molecular features of pulmonary pleomorphic carcinoma (PPC) is insufficient. Here, we performed next-generation sequencing to determine the genomic and transcriptomic profiles of PPC. We sequenced the DNAs and RNAs of 78 specimens from 52 patients with PPC. We analyzed 15 PPC cases to identify intratumoral differences in gene alterations, tumor mutation burden (TMB), RNA expression, and PD-L1 expression between epithelial and sarcomatoid components. The genomic alterations of six cases of primary tumors and corresponding metastatic tumors were analyzed. KRAS mutations (27%) were the most common driver mutations, followed by EGFR (8%), and MET (8%) mutations. Epithelial and sarcomatoid components shared activating driver mutations, and there were no significant differences in CD274 expression or TMB between the two components. However, PD-L1 was highly expressed in the sarcomatoid component of several cases compared with the epithelial component. Primary and metastatic tumors shared oncogenic mutations among genes such as KRAS and TP53, and additional alterations including NOTCH4 mutations were specifically identified in the metastatic regions. Our data suggest that therapies targeting activating driver mutations may be effective for patients with PPC and that immune checkpoint inhibitors of PPC may be recommended after careful assessment of PD-L1 expression in each epithelial and sarcomatoid component. - Loss of H3K27 trimethylation is frequent in IDH1-R132H but not in non-canonical IDH1/2 mutated and 1p/19q codeleted oligodendroglioma: a Japanese cohort study
Umma Habiba, Hirokazu Sugino, Roumyana Yordanova, Koki Ise, Zen-ichi Tanei, Yusuke Ishida, Satoshi Tanikawa, Shunsuke Terasaka, Ken-ichi Sato, Yuuta Kamoshima, Masahiko Katoh, Motoo Nagane, Junji Shibahara, Masumi Tsuda, Shinya Tanaka
Acta Neuropathologica Communications, 9, 1, 95, 95, Springer Science and Business Media LLC, 2021年05月21日, [査読有り], [国際誌]
英語, 研究論文(学術雑誌),Abstract Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH )1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing. - 脊髄capillary hemangiomaの臨床病理学的特徴
種井 善一, 津田 真寿美, 谷川 聖, 杉野 弘和, 石田 雄介, 大竹 安史, 今村 博幸, 小柳 泉, 飛騨 一利, 田中 伸哉
Brain Tumor Pathology, 38, Suppl., 119, 119, 日本脳腫瘍病理学会, 2021年05月
日本語 - Rapid reprogramming of tumour cells into cancer stem cells on double-network hydrogels
Jun Suzuka, Masumi Tsuda, Lei Wang, Shinji Kohsaka, Karin Kishida, Shingo Semba, Hirokazu Sugino, Sachiyo Aburatani, Martin Frauenlob, Takayuki Kurokawa, Shinya Kojima, Toshihide Ueno, Yoshihiro Ohmiya, Hiroyuki Mano, Kazunori Yasuda, Jian Ping Gong, Shinya Tanaka
Nature Biomedical Engineering, 5, 8, 914, 925, Springer Science and Business Media LLC, 2021年03月29日, [査読有り]
研究論文(学術雑誌) - Involvement of BMP and Wnt Signals Leadingto Epithelial-Mesenchymal Transition in Colon Adenocarcinoma with Heterotopic Ossification.
Naho Katono, Masumi Tsuda, Jun Suzuka, Yoshitaka Oda, Lei Wang, Zen-Ichi Tanei, Mishie Tanino, Takanobu Ohata, Eisuke Nagabuchi, Yusuke Ishida, Shunsuke Kimura, Toshihiko Iwanaga, Shinya Tanaka
Annals of clinical and laboratory science, 51, 2, 271, 276, 2021年03月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Here we present the case of a 73-year-old male with rectal adenocarcinoma with heterotopic ossification (HO). Cancer-associated HO in the digestive system is rare. Thus, the precise mechanism and clinicopathological significance of HO have not yet been defined. To clarify the molecular mechanisms of HO, we analyzed the expression levels of signaling molecules related to epithelial-mesenchymal transition (EMT) that lead to ossification in the tumor cells discriminating the ossified area (HO-area) and non-ossified area (non-HO area). Expression levels of BMP4 were elevated in both areas, whereas BMP2 was specifically increased in the HO-area by qPCR. EMT-related molecules such as Snail and Slug were especially higher in the HO-area. By immunohistochemistry, the expression of Smad4, nuclear staining of β-catenin, and the phosphorylated form of GSK-3β were detectable in both areas, and GSK-3β was highly phosphorylated in the HO-area. The tumor growth rate was extremely high, with the Ki-67 labeling index at 90%. In the HO-area, osteoblasts with alkaline phosphatase expression were distributed surrounding the tumor cells. This is the first demonstration of the involvement of EMT in HO of colon cancer through BMP/SMAD and WNT/β-catenin signaling pathways, which are especially prominent in the HO-area leading to the osteogenic property. - Isotope Microscopic Observation of Osteogenesis Process Forming Robust Bonding of Double Network Hydrogel to Bone
Takayuki Nonoyama, Lei Wang, Masumi Tsuda, Yuki Suzuki, Ryuji Kiyama, Kazunori Yasuda, Shinya Tanaka, Kousuke Nagata, Ryosuke Fujita, Naoya Sakamoto, Noriyuki Kawasaki, Hisayoshi Yurimoto, Jian Ping Gong
Advanced Healthcare Materials, 2001731, 2001731, Wiley, 2020年11月16日, [査読有り]
研究論文(学術雑誌) - CMKLR1は肝癌幹細胞標的治療のための候補分子である
谷 道夫, 津田 真寿美, 鈴鹿 淳, 王 磊, 武冨 紹信, 田中 伸哉
日本癌学会総会記事, 79回, PJ14, 1, (一社)日本癌学会, 2020年10月
英語 - CMKLR1は肝癌幹細胞標的治療のための候補分子である
谷 道夫, 津田 真寿美, 鈴鹿 淳, 王 磊, 武冨 紹信, 田中 伸哉
日本癌学会総会記事, 79回, PJ14, 1, (一社)日本癌学会, 2020年10月
英語 - Chitin-Based Double-Network Hydrogel as Potential Superficial Soft-Tissue-Repairing Materials
Junchao Huang, Martin Frauenlob, Yuki Shibata, Lei Wang, Tasuku Nakajima, Takayuki Nonoyama, Masumi Tsuda, Shinya Tanaka, Takayuki Kurokawa, Jian Ping Gong
Biomacromolecules, American Chemical Society (ACS), 2020年09月27日, [査読有り]
研究論文(学術雑誌) - バイオマテリアルによる肝癌幹細胞の新規誘導法の開発とその解析
谷 道夫, 津田 真寿美, 鈴鹿 淳, 王 磊, 杉野 弘和, 谷川 聖, 石田 雄介, グン 剣萍, 田中 伸哉, 武冨 紹信
日本外科学会定期学術集会抄録集, 120回, DP, 6, (一社)日本外科学会, 2020年08月
日本語 - バイオマテリアルによる肝癌幹細胞の新規誘導法の開発とその解析
谷 道夫, 津田 真寿美, 鈴鹿 淳, 王 磊, 杉野 弘和, 谷川 聖, 石田 雄介, グン 剣萍, 田中 伸哉, 武冨 紹信
日本外科学会定期学術集会抄録集, 120回, DP, 6, (一社)日本外科学会, 2020年08月
日本語 - Synthetic PAMPS Gel Induces Chondrogenic Differentiation of ATDC5 Cells via a Novel Protein Reservoir Function
Shingo Semba, Nobuto Kitamura, Masumi Tsuda, Keiko Goto, Sadamu Kurono, Yoshihiro Ohmiya, Takayuki Kurokawa, Jian Ping Gong, Kazunori Yasuda, Shinya Tanaka
Journal of Biomedical Materials Research Part A, 2020年06月, [査読有り]
英語, 研究論文(学術雑誌) - Integrin α4 Mediates ATDC5 Cell Adhesion to Negatively Charged Synthetic Polymer Hydrogel Leading to Chondrogenic Differentiatio
Daiki Hashimoto, Shingo Semba, Masumi Tsuda, Takayuki Kurokawa, Nobuto Kitamura, Kazunori Yasuda, Jian Ping Gong, Shinya Tanaka
Biochemical and Biophysical Research Communications, 528, 1, 120, 126, 2020年05月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Negatively charged synthetic hydrogels have been known to facilitate various cellular responses including cell adhesion, proliferation, and differentiation; however, the molecular mechanism of hydrogel-dependent control of cell behavior remains unclear. Recently, we reported that negatively charged poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) gel induces chondrogenic differentiation of ATDC5 cells via novel protein reservoir function. In this study, we identified the cell adhesion molecules binding to PAMPS gels that act as mechanoreceptors. First, we performed a pull-down assay by particle gels using cell membrane proteins of ATDC5, and found that multiple membrane proteins bound to the PAMPS gel, whereas the uncharged poly(N,N'-dimethylacrylamide) gel as control did not bind to any membrane proteins. Western blot analysis indicated differential binding of integrin (ITG) isoforms to the PAMPS gel, in which the α4 isoform, but not α5 and αv, efficiently bound to the PAMPS gel. ITG α4 knockdown decreased cell spreading of ATDC5 on PAMPS gels, whereas the enhanced expression increased the behavior. Furthermore, ITG α4 depletion suppressed PAMPS gel-induced expression of bone morphogenic protein (BMP) 4 contributing to chondrogenic differentiation, in concordance with the reduction of ERK activation. These results demonstrated that membrane protein binding to PAMPS gels occurred in a charge-dependent manner, and that ITG α4 plays a crucial role in cell spreading on PAMPS gels and acts as a mechanoreceptor triggering cellular signaling leads to chondrogenic differentiation. - Signaling adaptor protein Crk is involved in malignant feature of pancreatic cancer associated with phosphorylation of c-Met.
Satoko Uemura, Lei Wang, Masumi Tsuda, Jun Suzuka, Satoshi Tanikawa, Hirokazu Sugino, Toru Nakamura, Tomoko Mitsuhashi, Satoshi Hirano, Shinya Tanaka
Biochemical and biophysical research communications, 524, 2, 378, 384, 2020年04月02日, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Signaling adaptor protein Crk has been shown to play an important role in various human cancers. Crk links tyrosine kinases and guanine nucleotide exchange factors (GEFs) such as C3G and Dock180 to activate small G-proteins Rap and Rac, respectively. In pancreatic cancer, various molecular targeted therapies have provided no significant therapeutic benefit for the patients so far due to constitutive activation of KRAS by frequent KRAS mutation. Therefore, the establishment of novel molecular targeted therapy in KRAS-independent manner is required. Here, we investigated a potential of Crk as a therapeutic target in pancreatic cancer. Immunohistochemistry on human pancreatic cancer specimens revealed that the patients with high expression of Crk had a worse prognosis than those with low expression. We established Crk-knockdown pancreatic cancer cells by siRNA using PANC-1, AsPC-1, and MIA PaCa-2 cells, which showed decreased cell proliferation, invasion, and adhesion. In Crk-knockdown pancreatic cancer cells, the decrease of c-Met phosphorylation was observed. In the orthotopic xenograft model, Crk depletion prolonged survival of mice significantly. Thus, signaling adaptor protein Crk is involved in malignant potential of pancreatic cancer associated with decrease of c-Met phosphorylation, and Crk can be considered to be a potential therapeutic molecular target. - Cisplatin Relocalizes RNA Binding Protein HuR and Enhances the Oncolytic Activity of E4orf6 Deleted Adenovirus
Umma Habiba, Elora Hossain, Aya Yanagawa-Matsuda, Abu Faem Mohammad Almas Chowdhury, Masumi Tsuda, Asad-uz- Zaman, Shinya Tanaka, Fumihiro Higashino
Cancers, 12, 4, 809, 809, MDPI AG, 2020年03月27日, [査読有り]
英語, 研究論文(学術雑誌), The combination of adenoviruses and chemotherapy agents is a novel approach for human cancer therapeutics. A meticulous analysis between adenovirus and chemotherapeutic agents can help to design an effective anticancer therapy. Human antigen R (HuR) is an RNA binding protein that binds to the AU-rich element (ARE) of specific mRNA and is involved in the export and stabilization of ARE-mRNA. Our recent report unveiled that the E4orf6 gene deleted oncolytic adenovirus (dl355) replicated for certain types of cancers where ARE-mRNA is stabilized. This study aimed to investigate whether a combined treatment of dl355 and Cis-diamminedichloroplatinum (CDDP) can have a synergistic cell-killing effect on cancer cells. We confirmed the effect of CDDP in nucleocytoplasmic HuR shuttling. In vitro and in vivo experiments showed the enhancement of cancer cell death by apoptosis induction and a significant reduction in tumor growth following combination treatment. These results suggested that combination therapy exerted a synergistic antitumor activity by upregulation of CDDP induced cytoplasmic HuR, which led to ARE mRNA stabilization and increased virus proliferation. Besides, the enhanced cell-killing effect was due to the activation of the intrinsic apoptotic pathway. Therefore, the combined treatment of CDDP and dl355 could represent a rational approach for cancer therapy. - Emery-Dreifuss型筋ジストロフィーに伴う心不全の1剖検例
五味川 龍, 石田 雄介, 桑原 健, 石垣 隆弘, 谷川 聖, 小田 義崇, 王 磊, 杉野 弘和, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 109, 1, 492, 492, (一社)日本病理学会, 2020年03月
日本語 - 前立腺癌のGleason pattern評価のためのSemantic segmentationモデル及びRaspberry Pi端末を用いた応用
遠田 建, 伊勢 昂生, 石田 雄介, 桑原 健, 谷川 聖, 小田 義崇, 王 磊, 杉野 弘和, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 109, 1, 496, 496, (一社)日本病理学会, 2020年03月
日本語 - 新規変異BRAFV601K変異を認める良性脳腫瘍(毛様体性星細胞腫)の一例
榎枝 未紗, 小田 義崇, 津田 真寿美, 飛弾 一利, 杉野 弘和, 谷川 聖, 鈴鹿 淳, 王 磊, 石田 雄介, 田中 伸哉
日本病理学会会誌, 109, 1, 497, 497, (一社)日本病理学会, 2020年03月
日本語 - Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer: A Novel Therapeutic Target.
Toshihiro Kushibiki, Toru Nakamura, Masumi Tsuda, Takahiro Tsuchikawa, Koji Hontani, Kazuho Inoko, Mizuna Takahashi, Toshimichi Asano, Keisuke Okamura, Soichi Murakami, Yo Kurashima, Yuma Ebihara, Takehiro Noji, Yoshitsugu Nakanishi, Kimitaka Tanaka, Nako Maishi, Katsunori Sasaki, Woong-Ryeon Park, Toshiaki Shichinohe, Kyoko Hida, Shinya Tanaka, Satoshi Hirano
Molecular cancer therapeutics, 19, 1, 187, 198, 2020年01月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Over the past 30 years, the therapeutic outcome for pancreatic ductal adenocarcinoma (PDAC) has remained stagnant due to the lack of effective treatments. We performed a genome-wide analysis to identify novel therapeutic targets for PDAC. Our analysis showed that Homo sapiens chromosome 16 open reading frame 74 (C16orf74) was upregulated in most patients with PDAC and associated with poor prognosis. Previously, we demonstrated that C16orf74 interacts with the catalytic subunit alpha of protein phosphatase 3 and plays an important role in PDAC invasion. However, the pathophysiologic function of C16orf74 is still unclear. In this study, through the analysis of C16orf74 interaction, we demonstrate a new strategy to inhibit the growth and invasion of PDAC. C16orf74 exists in the homodimer form under the cell membrane and binds integrin αVβ3 and is also involved in invasion by activating Rho family (Rac1) and MMP2. Considering that this dimeric form was found to be involved in the function of C16orf74, we designed an 11R-DB (dimer block) cell-permeable dominant-negative peptide that inhibits the dimer form of C16orf74. 11R-DB suppressed invasion and proliferation of PDAC cell lines by inhibiting phosphorylation of Akt and mTOR and also by inactivation of MMP2. 11R-DB also showed antitumor effects in an orthotopic xenograft model and peritoneal metastasis model. Thus, this study demonstrates that dimerized C16orf74, present in the cell membrane, is involved in pancreatic cancer invasion and proliferation. In addition, the C16orf74 dimer block cell-permeable peptide (11R-DB) has a potent therapeutic effect on PDAC in vitro and in vivo. - Clinical efficacy and safety of first-line nilotinib therapy and evaluation of the clinical utility of the FRET-based drug sensitivity test
Kondo T, Fujioka M, Fujisawa S, Sato K, Tsuda M, Miyagishima T, Mori A, Iwasaki H, Kakinoki Y, Yamamoto S, Haseyama Y, Ando S, Shindo M, Ota S, Kurosawa M, Ohba Y, Teshima T, North Japan, Hematology Study Group, NJHSG
Int J Hematol, 110, 4, 482, 489, 2019年10月, [査読有り] - Autopsy findings in the early stage of amyotrophic lateral sclerosis with "dropped head" syndrome.
Tanikawa S, Tanino M, Wang L, Ishikawa M, Miyazaki M, Tsuda M, Orba Y, Sawa H, Matoba K, Nakamura N, Nagashima K, Hall WW, Tanaka S
Neuropathology : official journal of the Japanese Society of Neuropathology, 39, 5, 374, 377, 2019年10月, [査読有り] - Modulation and Characterization of the Double Network Hydrogel Surface-bulk Transition
Martin Frauenlob, Daniel R. King, Honglei Guo, Seiichiro Ishihara, Masumi Tsuda, Takayuki Kurokawa, Hisashi Haga, Shinya Tanaka, Jian Ping Gong
Macromolecules, 52, 17, 6704, 6713, 2019年08月, [査読有り]
英語, 研究論文(学術雑誌) - Exosomes containing ErbB2/CRK induce vascular growth in premetastatic niches and promote metastasis of bladder cancer.
Yoshida K, Tsuda M, Matsumoto R, Semba S, Wang L, Sugino H, Tanino M, Kondo T, Tanabe K, Tanaka S
Cancer science, 110, 7, 2119, 2132, 2019年07月, [査読有り], [責任著者], [国際誌]
英語, Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin-based combination chemotherapy have been developed. Therefore, it is an urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM-UC-3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM-UC-3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM-UC-3-derived exosomes in a CRK-dependent manner; the exosomes significantly increased proliferation and invasion properties of low-grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM-UC-3-derived exosomes, i.v. implanted UM-UC-3 cells were trapped with surrounding PKH67-labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK-depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC. - バイオマテリアルによる肝癌幹細胞の新規誘導法
谷 道夫, 津田 真寿美, 鈴鹿 淳, 王 磊, 杉野 弘和, 谷川 聖, 石田 雄介, グン 剣萍, 田中 伸哉, 武冨 紹信
日本外科学会定期学術集会抄録集, 119回, PS, 6, (一社)日本外科学会, 2019年04月
日本語 - 病理IT化、情報化とAI研究 病理診断と人工知能 スタートアップから脳腫瘍への応用まで
石田 雄介, 桑原 健, 小田 義崇, 谷川 聖, 杉野 弘和, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 108, 1, 192, 192, (一社)日本病理学会, 2019年04月
日本語 - 解剖で偶然見つかった無症候性胸髄内神経鞘腫の一例
有田 梨乃, 谷川 聖, 津田 真寿美, 石田 雄介, 杉野 弘和, 田中 伸哉
日本病理学会会誌, 108, 1, 459, 459, (一社)日本病理学会, 2019年04月
日本語 - 髄膜腫におけるTERTプロモーター遺伝子変異の検討
久世 瑞穂, 小田 義崇, 津田 真寿美, 湯澤 明夏, 谷川 聖, 杉野 弘和, 石田 雄介, 田中 伸哉
日本病理学会会誌, 108, 1, 463, 463, (一社)日本病理学会, 2019年04月
日本語 - 次世代シーケンサーを用いた肺原発多形癌の遺伝子変異解析
長野 匡晃, 高阪 真路, 牛久 綾, 林 大久生, 田中 伸哉, 津田 真寿美, 篠原 敏也, 大森 優子, 菅谷 文子, 加藤 弘明, 成田 吉明, 高持 一矢, 鈴木 健司, 中島 淳, 間野 博行
日本呼吸器外科学会雑誌, 33, 3, RO1, 3, (NPO)日本呼吸器外科学会, 2019年04月, [査読有り]
日本語 - "Integrated diagnosis" of pilocytic astrocytoma: Molecular diagnostic procedure for an unusual case.
Ishida Y, Tsuda M, Sawamura Y, Fujii K, Murai H, Horiuchi N, Orba Y, Sawa H, Hall WW, Nagashima K, Tanaka S
Pathology international, 68, 12, 694, 699, 2018年12月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), A 24 year-old female presented with a mass lesion in the right temporal lobe. This case was difficult to diagnose using histological and immunological methods and therefore molecular analyses were applied to provide a definitive diagnosis. The tumor was well-demarcated, partially cystic, and irregularly-enhanced on gadolinium-enhanced T1-weighted magnetic resonance images. Pathologically, a large part of the tumor consisted of cells with fine cytoplasmic processes on a myxoid and mucinous background. Cells formed a microcystic structure around the mucinous tissue. Numerous eosinophilic granular bodies, but not Rosenthal fibers, were present. The solid and compact regions of the tumor were composed of fasciculation of dense fibrous glial tissues and occasional multinucleated giant cells. Tumor cells and their fragmented cytoplasmic processes were positively stained with GFAP, while eosinophilic granular bodies were both positive and negative. Xanthomatous changes were not detected and the reticulin fibers were restricted to vascular tissues. The MIB1 index was scored as approximately 10%. In molecular analyses of BRAF, the KIAA1549-BRAF (K16-B9) fusion gene was detected in all tumor regions, whereas BRAF V600E mutation was not detected by either conventional Sanger sequencing or the Eprobe-PCR method. Based on the results of the molecular analyses, this case was diagnosed as pilocytic astrocytoma. - 馬尾原発の髄外性形質細胞腫の1例
小田 義崇, 杉野 弘和, 小柳 泉, 谷川 聖, 石田 雄介, 津田 真寿美, 田中 伸哉
Brain Tumor Pathology, 35, Suppl., 177, 177, 日本脳腫瘍病理学会, 2018年09月
日本語 - Pre-treatment evaluation of FRET-based drug sensitivity test for patients with CML treated with dasatinib.
Kondo T, Fujioka M, Tsuda M, Murai K, Yamaguchi K, Miyagishima T, Shindo M, Nagashima T, Wakasa K, Fujimoto N, Yamamoto S, Yonezumi M, Saito S, Sato S, Ogawa K, Chou T, Watanabe R, Kato Y, Takahashi S, Okano Y, Yamamoto J, Ohta M, Iijima H, Oba K, Kishino S, Sakamoto J, Ishida Y, Ohba Y, Teshima T, Inter-Michinoku Dasatinib, Study Group, IMIDAS
Cancer science, 109, 7, 2256, 2265, 2018年07月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358). - Pathologic Findings and Clinical Course of Midline Paraventricular Gliomas Diagnosed Using a Neuroendoscope
Shinjiro Fukami, Nobuyuki Nakajima, Hirofumi Okada, Jiro Akimoto, Tamotsu Miki, Hirokazu Fukuhara, Yukiko Shishido-Hara, Toshitaka Nagao, Masumi Tsuda, Michihiro Kohno
World Neurosurgery, 114, e366, e377, Elsevier Inc., 2018年06月01日, [査読有り]
英語, 研究論文(学術雑誌), Introduction: Removal of midline paraventricular gliomas is difficult because of their deep localization and invasive character, requiring biopsy for pathologic diagnosis. This study aimed to assess the pathologic findings and clinical course of midline paraventricular gliomas diagnosed using a neuroendoscope. Methods: This study was performed as a retrospective investigation using a neuroendoscope of 26 patients whose tumors were diagnosed as midline paraventricular gliomas. The main loci of the lesions were the thalamus (11 patients), tectum (6 patients), and other areas (9 patients). Of these 26 patients, 21 (81%) had accompanying obstructive hydrocephalus. Surgery was performed via the lateral ventricle using a flexible scope. For patients with obstructive hydrocephalus, we added endoscopic third ventriculostomy, septostomy, and/or plasty of the foramen of Monro. Pathologic diagnosis was determined according to hematoxylin-eosin staining and immunohistochemistry using anti-GFAP, anti-Ki-67, anti-H3-K27M, and anti-IDH1-R132H antibodies. Results: The pathologic diagnoses were grade I (5 patients), grade II (3 patients), grade III (6 patients), and grade IV (4 patients) gliomas. Six patients were diagnosed as having high-grade glioma, which was difficult to distinguish between grade III and grade IV. Two patients were undiagnosable. H3-K27M was strongly positive in 8 of 15 patients with high-grade glioma. All patients with high-grade gliomas died or received best supportive care within 2 years after surgery. Conclusions: Neuroendoscopic surgery is useful for midline paraventricular gliomas in terms of the treatment of obstructive hydrocephalus, as well as pathologic diagnosis and genetic analysis, which are required under the World Health Organization 2016 classification. - Tumor budding and human chorionic gonadotropin-β expression correlate with unfavorable patient outcome in colorectal carcinoma.
Konishi Y, Kawamata F, Nishihara H, Homma S, Kato Y, Tsuda M, Kohsaka S, Einama T, Liu C, Yoshida T, Nagatsu A, Tanino M, Tanaka S, Kawamura H, Kamiyama T, Taketomi A
Medical oncology (Northwood, London, England), 35, 7, 104, HUMANA PRESS INC, 2018年06月, [査読有り]
英語, 研究論文(学術雑誌), Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-beta (hCG beta) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCG beta expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCG beta positive on immunohistochemistry. More tumor buds were present in the hCG beta-positive cases (P < 0.01), and tumor budding was significantly correlated with hCG beta positivity (P < 0.01). Cases with both tumor budding and hCG beta expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCG beta expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an "EMT phenotype" who may respond to targeted molecular therapies. - Tough and Self-Recoverable Thin Hydrogel Membranes for Biological Applications
Ya Nan Ye, Martin Frauenlob, Lei Wang, Masumi Tsuda, Tao Lin Sun, Kunpeng Cui, Riku Takahashi, Huijie Zhang, Tasuku Nakajima, Takayuki Nonoyama, Takayuki Kurokawa, Shinya Tanaka, Jian Ping Gong
Advanced Functional Materials, 28, 31, 1801489, WILEY-V C H VERLAG GMBH, 2018年06月, [査読有り]
英語, 研究論文(学術雑誌), Tough and self-recoverable hydrogel membranes with micrometer-scale thickness are promising for biomedical applications, which, however, rarely be realized due to the intrinsic brittleness of hydrogels. In this work, for the first time, by combing noncovalent DN strategy and spin-coating method, we successfully fabricated thin (thickness: 5-100 mu m), yet tough (work of extension at fracture: 10(5)-10(7) J m(-3)) and 100% self-recoverable hydrogel membranes with high water content (62-97 wt%) in large size (approximate to 100 cm(2)). Amphiphilic triblock copolymers, which form physical gels by self-assembly, were used for the first network. Linear polymers that physically associate with the hydrophilic midblocks of the first network, were chosen for the second network. The inter-network associations serve as reversible sacrificial bonds that impart toughness and self-recovery properties on the hydrogel membranes. The excellent mechanical properties of these obtained tough and thin gel membranes are comparable, or even superior to many biological membranes. The in vitro and in vivo tests show that these hydrogel membranes are biocompatible, and postoperative nonadhesive to neighboring organs. The excellent mechanical and biocompatible properties make these thin hydrogel membranes potentially suitable for use as biological or postoperative antiadhesive membranes. - 新規技術を用いた新しい研究アプローチ 高分子ハイドロゲルによる癌幹細胞へのリプログラミング誘導技術
津田 真寿美, 鈴鹿 淳, 王 磊, 仙葉 慎吾, 油谷 幸代, 黒川 孝幸, 近江谷 克裕, 安田 和則, グン 剣萍, 田中 伸哉
日本病理学会会誌, 107, 1, 217, 217, (一社)日本病理学会, 2018年04月
日本語 - 神経再生工学における両電荷を有するハイドロゲルの開発
谷川 聖, 仙葉 慎吾, 津田 真寿美, 王 磊, 谷野 美智枝, 石田 雄介, 杉野 弘和, 鈴鹿 淳, 田中 伸哉
日本病理学会会誌, 107, 1, 329, 329, (一社)日本病理学会, 2018年04月
日本語 - 悪性神経膠腫におけるIDH1遺伝子変異による放射線照射後変化の解析(Analysis of the effect of IDH1 mutation on the radiosensitivity in malignant glioma)
北崎 アリサ, 谷野 美智枝, 九笹 めい, 杉野 弘和, 王 磊, 石田 雄介, 津田 真寿美, 五十嵐 香織, 曽我 朋義, 田中 伸哉
日本病理学会会誌, 107, 1, 379, 379, (一社)日本病理学会, 2018年04月
英語 - 脳腫瘍組織像の画像解析と遺伝子プロファイルに対応したDeep-Learning法の応用
石田 雄介, 杉野 弘和, 谷野 美智枝, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 107, 1, 380, 380, (一社)日本病理学会, 2018年04月
日本語 - 悪性中皮腫におけるOTUB1の役割
九笹 めい, 谷野 美智枝, 北崎 アリサ, 杉野 弘和, 石田 雄介, 王 磊, 津田 真寿美, 高澤 啓, 平野 博嗣, 田中 伸哉
日本病理学会会誌, 107, 1, 406, 406, (一社)日本病理学会, 2018年04月
日本語 - 中枢神経系に生じたメトトレキサート関連リンパ増殖性疾患の一例
杉野 弘和, 佐藤 憲市, 笠井 康弘, 孫 慧, 石田 雄介, 谷野 美智枝, 津田 真寿美, 松野 吉宏, 田中 伸哉
日本病理学会会誌, 107, 1, 449, 449, (一社)日本病理学会, 2018年04月
日本語 - 脳死肝移植後に感染源不明の敗血症を繰り返し死亡した一例の死後画像および病理解剖所見
伊勢 昂生, 山下 たんぽぽ, 石田 雄介, 桑原 健, 川村 典生, 菊池 穏香, 杉野 弘和, 谷野 美智枝, 津田 真寿美, 田中 伸哉
日本病理学会会誌, 107, 1, 530, 530, (一社)日本病理学会, 2018年04月
日本語 - Tough and Self‐Recoverable Thin Hydrogel Membranes for Biological Applications
Ye YN, Frauenlob M, Wang L, Tsuda M, Sun TL, Cui K, Takahashi R, Ahang HJ, Nakajima T, Nonoyama T, Kurokawa T, Tanaka S, Gong JP
Advanced Functional Materials, 29, 1801489, 1, 11, 2018年03月, [査読有り] - miR-23a promotes invasion of glioblastoma via HOXD10-regulated glial-mesenchymal transition.
Yachi K, Tsuda M, Kohsaka S, Wang L, Oda Y, Tanikawa S, Ohba Y, Tanaka S
Signal transduction and targeted therapy, 3, 33, 2018年, [査読有り], [筆頭著者] - Adaptor protein CRK promotes tumor progression and metastasis of bladder cancer by regulating ErbB2 in exosome
Tsuda Masumi, Yoshida Kazuhiko, Matsumoto Ryuji, Kondo Tsunenori, Shinohara Nobuo, Tanaka Shinya
CANCER SCIENCE, 109, 121, 2018年01月, [査読有り] - Chorionic Gonadotropin-β Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis.
Kawamata F, Nishihara H, Homma S, Kato Y, Tsuda M, Konishi Y, Wang L, Kohsaka S, Liu C, Yoshida T, Tanino M, Tanaka S, Kawamura H, Kamiyama T, Taketomi A
The American journal of pathology, 188, 1, 204, 215, 2018年01月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), Ectopic production of free β human chorionic gonadotropin (hCGβ) has been associated with aggressive behavior in non-trophoblastic tumors. hCGβ shares common evolutionary sequences with transforming growth factor-β (TGF-β), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGβ during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGβ-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGβ positivity [13/80 (16.3%)] was lower than serologic hCGβ positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGβ-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGβ altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGβ-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-β receptor inhibitors (P < 0.05). hCGβ thus induces EMT via the TGF-β signaling pathway, and it may represent a molecular target in CRC treatment. - A clinicopathological analysis of six autopsy cases of sudden unexpected death due to infectious aortitis in patients with aortic tears
Marin Ishikawa, Mishie Ann Tanino, Masaya Miyazaki, Taichi Kimura, Yusuke Ishida, Lei Wang, Masumi Tsuda, Hiroshi Nishihara, Kazuo Nagashima, Shinya Tanaka
Internal Medicine, 57, 10, 1375, 1380, Japanese Society of Internal Medicine, 2018年, [査読有り]
英語, 研究論文(学術雑誌), Objective Cardiovascular disease is a leading cause of sudden unexpected death even in hospitalized patients. Infectious aortitis is a rare disease that has the potential to cause aortic tears and hemorrhage followed by sudden death. The aim of this study was to reveal the clinicopathological features of infectious aortitis that are related to sudden unexpected death. Methods We retrospectively reviewed 1,310 autopsy cases over 15 years and selected the cases involving patients who died suddenly due to aortic tears. We analyzed the clinical information and pathological findings. Results One hundred thirty-three of 1,310 cases (10.2%) were autopsied under the clinical diagnosis of unexpected sudden death. Aortic tears were identified in 33 cases (2.5%) and infectious aortitis was diagnosed in 6 (18.2%) of these cases. All cases involved male patients (middle-aged to elderly) with risk factors for atherosclerosis (i.e., hypertension). The laboratory data showed continuous leukocytosis and C-reactive protein elevation, even during the improvement phase, in patients with pre-existing infectious disease. The autopsy findings revealed three types of aortic tears (aneurysms, dissections and penetrating atherosclerotic ulcers with moderate to severe atherosclerosis), and the infiltration of numerous neutrophils at the site of rupture. Gram-positive bacteria were detected in four cases and Gram-negative bacteria were detected in two cases. Discussion We demonstrated that sudden unexpected death caused by infectious aortitis rarely occurred in hospitalized patients, even in the recovery phase of the preceding infectious disease. We therefore recommend that clinicians pay attention to infectious aortitis in patients with infectious disease, particularly elderly patients with atherosclerotic disease, even those who are in the improvement phase. Conclusion Unexpected sudden death by infectious aortitis in the recovery phase of antecedent infection. - ハイドロゲルを用いた癌幹細胞新規誘導法の開発
鈴鹿 淳, 津田 真寿美, 王 磊, 仙葉 愼吾, 油谷 幸代, 黒川 孝幸, 近江谷 克裕, 安田 和則, きょう 剣萍, 田中 伸哉
生命科学系学会合同年次大会, 2017年度, [1P, 0964], 生命科学系学会合同年次大会運営事務局, 2017年12月
日本語 - 悪性中皮腫におけるOTUB1の発現
九笹 めい, 谷野 美智枝, 北崎 アリサ, 杉野 弘和, 石田 雄介, 王 磊, 津田 真寿美, 高澤 啓, 平野 博嗣, 田中 伸哉
日本癌学会総会記事, 76回, P, 3277, 日本癌学会, 2017年09月
英語 - 多形黄色星細胞腫におけるBRAF遺伝子変異(BRAF V600E)とp16の発現の検討
谷野 美智枝, 南條 博, 津田 真寿美, 杉野 弘和, 王 磊, 石田 雄介, 田中 伸哉
日本癌学会総会記事, 76回, P, 3317, 日本癌学会, 2017年09月
英語 - 悪性神経膠腫においてIDH1遺伝子変異は放射線照射後のアポトーシスを亢進する
北崎 アリサ, 谷野 美智枝, 九笹 めい, 杉野 弘和, 王 磊, 石田 雄介, 仙葉 慎吾, 津田 真寿美, 五十嵐 香織, 曽我 朋義, 田中 伸哉
日本癌学会総会記事, 76回, P, 3323, 日本癌学会, 2017年09月
英語 - Notch 1 regulates invasion and metastasis of head and neck squamous cell carcinoma by inducing EMT through c-Myc
Naoya Inamura, Taichi Kimura, Lei Wang, Hiroko Yanagi, Masumi Tsuda, Mishie Tanino, Hiroshi Nishihara, Satoshi Fukuda, Shinya Tanaka
AURIS NASUS LARYNX, 44, 4, 447, 457, ELSEVIER SCI LTD, 2017年08月, [査読有り]
英語, 研究論文(学術雑誌), Objective: As 50% of patients of head and neck squamous carcinoma (HNSCC) exhibit poor prognosis, the identification of new therapeutic targets is required. Recently, there have been several reports about the correlation between Notch1 and HNSCC, but the precise mechanism is still obscure. Therefore, in this study, we examined the involvement of Notch I in HNSCC by using HNSCC cell lines and surgical specimens.
Methods: To investigate the role of Notch1 in HNSCC, we examined the effect of Notch inhibitor DAPT on cell growth, invasion, and tumorigenicity using five HNSCC cell lines in vitro and in vivo. We further examined that the correlation with Notch expression and clinical prognostic factors was evaluated by using 101 HNSCC surgical specimens.
Results: DAPT reduced the nuclear expression of Notch and c-Myc and repressed cell growth, EMT-dependent cell invasion in vitro, and tumorigenicity in vivo. An overexpression of Myc enhanced EMT with an increase of Snail and vimentin together with decreased levels of E-cadherin in HSC3 cells. Finally, we discovered that Notch expression was well correlated with MIB-1 index and lymph node metastases.
Conclusion: We discovered that Notch1 was strongly correlated with HNSCC growth, invasion, and metastases. Therefore, Notch1 might be a new therapeutic target and a predictive marker of proliferation and metastasis of HNSCC. (C) 2016 Elsevier Ireland Ltd. All rights reserved. - 実験講座 新しい技術 電界撹拌装置「ヒスト・テック R-IHC」による免疫組織化学染色の原理および臨床・研究応用への展開
森谷 純, 谷野 美智枝, 津田 真寿美, 田中 伸哉
生体の科学, 68, 4, 365, 370, 金原一郎記念医学医療振興財団 ; 1949-, 2017年07月
日本語 - THE ADAPTOR PROTEIN CRK-INDUCED ERBB2 EXPRESSION PROMOTES TUMOR PROGRESSION AND METASTASIS OF BLADDER CANCER VIA EXOSOMES
Yoshida Kazuhiko, Tsuda Masumi, Matsumoto Ryuji, Semba Shingo, Kimura Taichi, Tanino Mishie, Nishihara Hiroshi, Kondo Tsunenori, Tanabe Kazunari, Tanaka Shinya
JOURNAL OF UROLOGY, 197, 4, E1175, 2017年04月, [査読有り] - 皮膚悪性黒色腫に対するオプジーボ投与後に出現し免疫染色にてS-100陰性を呈した転移性脳腫瘍の1例
石田 雄介, 高橋 達郎, 佐藤 行真, 池田 正起, 守田 玲菜, 武井 英博, 木村 太一, 津田 真寿美, 谷野 美智枝, 田中 伸哉
日本病理学会会誌, 106, 1, 477, 477, (一社)日本病理学会, 2017年03月
日本語 - Clinicopathological evaluation of Sox10 expression in diffuse-type gastric adenocarcinoma
Marin Kato, Hiroshi Nishihara, Hideyuki Hayashi, Taichi Kimura, Yusuke Ishida, Lei Wang, Masumi Tsuda, Mishie Ann Tanino, Shinya Tanaka
MEDICAL ONCOLOGY, 34, 1, 8, HUMANA PRESS INC, 2017年01月, [査読有り]
英語, 研究論文(学術雑誌), Sox10, one of the transcription factors, regulates Wnt/beta-catenin signaling in diverse developmental processes in normal tissues. Sox10 is also expressed in variable solid tumors such as breast cancer, salivary tumor, hepatocellular carcinoma, ovarian tumor, nasopharyngeal carcinoma, prostate cancer, and digestive cancer. The role of Sox10 during tumorigenesis is still controversial, especially in digestive cancers; thus, we performed clinicopathological evaluation of Sox10 expression in 41 cases of diffuse-type gastric adenocarcinoma (DGA). We examined the expression of Sox10 by immunohistochemical staining and real-time quantitative reverse transcriptase PCR and evaluated the correlation between Sox10 expression and clinicopathological factors. A low-level expression of Sox10 was significantly associated with high-level venous invasion by immunohistochemical evaluation, while it was significantly associated with high-level lymphatic permeation when analyzed by real-time PCR assay. Survival analysis of 41 cases indicated that high level of vascular permeation was a statistically poor prognostic factor, suggesting that derogation of Sox10 would lead to unfavorable patients' outcome through the acceleration of vascular invasion. In this study, we revealed the clinical benefit of evaluation of Sox10 expression to predict the risk of vascular permeation which yields patients' poor prognosis in DGA. - Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma (vol 11, e0158888, 2016)
Satoshi Kawano, Alexandra R. Grassian, Masumi Tsuda, Sarah K. Knutson, Natalie M. Warholic, Galina Kuznetsov, Shanqin Xu, Yonghong Xiao, Roy M. Pollock, Jesse J. Smith, Kevin W. Kuntz, Scott Ribich, Yukinori Minoshima, Junji Matsui, Robert A. Copeland, Shinya Tanaka, Heike Keilhack
PLOS ONE, 12, 1, e0170539, PUBLIC LIBRARY SCIENCE, 2017年01月, [査読有り]
英語 - Aldo-keto reductase 1C1 induced by interleukin-1β mediates the invasive potential and drug resistance of metastatic bladder cancer cells.
Matsumoto R, Tsuda M, Yoshida K, Tanino M, Kimura T, Nishihara H, Abe T, Shinohara N, Nonomura K, Tanaka S
Scientific reports, 6, 34625, 34625, 2016年10月04日, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, and drug resistance are urgent to improving long-term patient survival. One of the metabolic enzymes, aldo-keto reductase 1C1 (AKR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. In orthotopic xenograft models of a human bladder cancer cell line, UM-UC-3, metastatic sublines were established from tumors in the liver, lung, and bone. These cells possessed elevated levels of EMT-associated markers, such as Snail, Slug, or CD44, and exhibited enhanced invasion. By microarray analysis, AKR1C1 was found to be up-regulated in metastatic lesions, which was verified in metastatic human bladder cancer specimens. Decreased invasion caused by AKR1C1 knockdown suggests a novel role of AKR1C1 in cancer invasion, which is probably due to the regulation of Rac1, Src, or Akt. An inflammatory cytokine, interleukin-1β, was found to increase AKR1C1 in bladder cancer cell lines. One particular non-steroidal anti-inflammatory drug, flufenamic acid, antagonized AKR1C1 and decreased the cisplatin-resistance and invasion potential of metastatic sublines. These data uncover the crucial role of AKR1C1 in regulating both metastasis and drug resistance; as a result, AKR1C1 should be a potent molecular target in invasive bladder cancer treatment. - 合成PAMPSゲルはタンパク質レザバーとして機能し、軟骨細胞ATDC5細胞に軟骨形成分化を誘導する(Synthetic PAMPS gel functions as protein reservoir, which induces a chondrogenic differentiation of chondrocytic ATDC5 cells)
仙葉 愼吾, 後藤 佳子, 北村 信人, 黒野 定, 近江谷 克裕, 津田 真寿美, 黒川 孝幸, グン・チェンピン, 田中 伸哉, 安田 和則
日本生化学会大会プログラム・講演要旨集, 89回, [1T18, 405)], (公社)日本生化学会, 2016年09月
英語 - BRAF V600E変異検索およびKIAA1549-BRAF融合遺伝子検索により診断に至った若年成人発症毛様細胞性星細胞腫
石田 雄介, 津田 真寿美, 澤村 豊, 村井 宏, 堀内 成好, 長嶋 和郎, 田中 伸哉
日本病理学会会誌, 105, 2, 75, 75, (一社)日本病理学会, 2016年09月
日本語 - Analysis of NAB2-STAT6 Gene Fusion in 17 Cases of Meningeal Solitary Fibrous Tumor/Hemangiopericytoma Review of the Literature
Sayaka Yuzawa, Hiroshi Nishihara, Lei Wang, Masumi Tsuda, Taichi Kimura, Mishie Tanino, Shinya Tanaka
AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 40, 8, 1031, 1040, LIPPINCOTT WILLIAMS & WILKINS, 2016年08月, [査読有り]
英語, Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a mesenchymal tumor that can affect virtually any region of the body. SFT/HPC of the thoracic cavity and soft tissue has been histologically considered a single biological entity termed SFT; in fact, NAB2-STAT6 gene fusion was recently identified in both diseases. In contrast, meningeal SFT and HPC still need to be investigated in detail with regard to gene fusion variants. The aim of this study was to verify the frequency of NAB2-STAT6 fusion and the relationship between fusion variants and clinicopathologic findings of SFT/HPC, especially meningeal SFT/HPC. We examined the NAB2-STAT6 fusion by reverse transcription polymerase chain reaction with 4 cases of meningeal SFT and 13 cases of meningeal HPC. NAB2-STAT6 fusion transcripts were identified in 12 of 17 cases, including NAB2ex6-STAT6ex17 (4/17, 24%), NAB2ex6-STAT6ex16 and NAB2ex4-STAT6ex2 (3/17, 18%, respectively), and NAB2ex5-STAT6ex16 (2/17, 12%). Three cases showed a pseudopapillary pattern, and 2 of them carried NAB2ex6-STAT6ex17. In addition, our meta-analysis revealed that the major fusion variant in meningeal SFT/HPC was NAB2ex6-STAT6ex16/17 (29/54, 54%), which was also common in soft tissue and intraperitoneum/retroperitoneum but rare in thoracic SFT. Fusion variant significantly correlated with age and histologic diagnosis in meningeal SFT/HPC but not with prognosis. Our results represented that meningeal SFT and HPC were in a single biological spectrum with NAB2-STAT6 gene fusion as was nonmeningeal SFT and further confirmed the organ-specific tumorigenic process and morphologic differences on the basis of fusion variants in meningeal SFT/HPC. - Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells
Kimura T, Wang L, Tabu K, Tsuda M, Tanino M, Maekawa A, Nishihara H, Hiraga H, Taga T, Oda Y, Tanaka S
Oncogene, 35, 30, 3932, 3943, Oncogene, 2016年07月28日
Synovial sarcoma accounts for almost 10% of all soft tissue sarcomas, and its prognosis is poor with 5-year survival rates at 36%. Thus, new treatments and therapeutic targets for synovial sarcoma are required. Tumor-initiating cells have been defined by the ability for self-renewal and multipotent differentiation, and they exhibit higher tumorigenic capacity, chemoresistance and radiation resistance, expecting to be a new therapeutic target. In synovial sarcoma, the presence of such stemness remains largely unclear; thus, we analyzed whether synovial sarcoma possessed tumor-initiating cells and explored specific markers, and we discovered that synovial sarcoma cell lines possessed heterogeneity by way of containing a sphere-forming subpopulation highly expressing NANOG, OCT4 and SOX2. By expression microarray analysis, CXCR4 was identified to be highly expressed in the sphere subpopulation and correlated with stem-cell-Associated markers. Inhibition of CXCR4 suppressed the cell proliferation of synovial sarcoma cell lines in vitro. The tumor-initiating ability of CXCR4-positive cells was demonstrated by xenograft propagation assay. CXCR4-positive cells showed higher tumorigenicity - Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system
Sayaka Yuzawa, Hiroshi Nishihara, Shigeru Yamaguchi, Hiromi Mohri, Lei Wang, Taichi Kimura, Masumi Tsuda, Mishie Tanino, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin, Norihiro Sato, Shinya Tanaka
MODERN PATHOLOGY, 29, 7, 708, 716, NATURE PUBLISHING GROUP, 2016年07月, [査読有り]
英語, 研究論文(学術雑誌), Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost effective. To establish a clinical sequencing system for meningioma and investigate the clinical significance of genotype, we retrospectively performed targeted amplicon sequencing on 103 meningiomas and evaluated the association with clinicopathological features. We designed amplicon-sequencing panels targeting eight genes including NF2 (neurofibromin 2), TRAF7, KLF4, AKT1, and SMO. Libraries prepared with genomic DNA extracted from PAXgenefixed paraffin-embedded tissues of 103 meningioma specimens were sequenced using the Illumina MiSeq. NF2 loss in some cases was also confirmed by interphase-fluorescent in situ hybridization. We identified NF2 loss and/or at least one mutation in NF2, TRAF7, KLF4, AKT1, and SMO in 81 out of 103 cases (79%) by targeted amplicon sequencing. On the basis of genetic status, we categorized meningiomas into three genotype groups: NF2 type, TRAKLS type harboring mutation in TRAF7, AKT1, KLF4, and/or SMO, and 'not otherwise classified' type. Genotype significantly correlated with tumor volume, tumor location, and magnetic resonance imaging findings such as adjacent bone change and heterogeneous gadolinium enhancement, as well as histopathological subtypes. In addition, multivariate analysis revealed that genotype was independently associated with risk of recurrence. In conclusion, we established a rapid clinical sequencing system that enables final confirmation of meningioma genotype within 7 days turnaround time. Our method will bring multiple benefits to neuropathologists and neurosurgeons for accurate diagnosis and appropriate postoperative management. - Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma
Satoshi Kawano, Alexandra R. Grassian, Masumi Tsuda, Sarah K. Knutson, Natalie M. Warholic, Galina Kuznetsov, Shanqin Xu, Yonghong Xiao, Roy M. Pollock, Jesse S. Smith, Kevin K. Kuntz, Scott Ribich, Yukinori Minoshima, Junji Matsui, Robert A. Copeland, Shinya Tanaka, Heike Keilhack
PLOS ONE, 11, 7, e0158888, PUBLIC LIBRARY SCIENCE, 2016年07月, [査読有り]
英語, 研究論文(学術雑誌), The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinicalstage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers. - Novel signaling collaboration between TGF-β and adaptor protein Crk facilitates EMT in human lung cancer.
Elmansuri AZ, Tanino MA, Mahabir R, Wang L, Kimura T, Nishihara H, Kinoshita I, Dosaka-Akita H, Tsuda M, Tanaka S
Oncotarget, 7, 19, 27094, 27107, IMPACT JOURNALS LLC, 2016年05月, [査読有り]
英語, 研究論文(学術雑誌), The signaling adaptor protein Crk has been shown to play an important role in various human cancers. However, its regulatory machinery is not clear. Here, we demonstrated that Crk induced EMT in A549 human lung adenocarcinoma cells through differential regulation of Rac1/Snail and RhoA/Slug, leading to decreased expression of E-cadherin and increased N-cadherin, fibronectin, and MMP2 expression. Cancer cells with mesenchymal features produced TGF-beta and also increased the levels of TGF-beta receptor. TGF-beta increased the endogenous levels of Crk and also augmented Crk-dependent expression of Snail and Slug, and conversely TGF-beta receptor inhibitor suppressed the levels of Snail and Slug. Overexpression of Crk was observed at the invasive front of human lung cancer tissues and was significantly associated with poor prognosis. Thus, TGF-beta and Crk collaborate to form a positive feedback loop to facilitate EMT, which may lead to the malignancy of human cancers possibly being affected by their microenvironment. - PAMPSゲルによるATDC5細胞のインスリン非依存性軟骨分化誘導シグナルの解明
後藤 佳子, 北村 信人, 和田 進, 安田 和則, 木村 太一, 津田 真寿美, 田中 伸哉, 仙葉 慎吾, 黒川 孝幸, グン・チェンピン
北海道整形災害外科学会雑誌, 57, 2, 287, 287, 北海道整形災害外科学会, 2016年04月
日本語 - Synthetic PAMPS gel activates BMP/Smad signaling pathway in ATDC5 cells, which plays a significant role in the gel-induced chondrogenic differentiation
Keiko Goto, Taichi Kimura, Nobuto Kitamura, Shingo Semba, Yoshihiro Ohmiya, Sachiyo Aburatani, Satoko Matsukura, Masumi Tsuda, Takayuki Kurokawa, Jian Ping Gong, Shinya Tanaka, Kazunori Yasuda
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A, 104, 3, 734, 746, WILEY-BLACKWELL, 2016年03月, [査読有り]
英語, 研究論文(学術雑誌), The purposes of this study were to identify signaling pathways that were specifically activated in ATDC5 cells cultured on poly (2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) gel in insulin-free maintenance medium and to evaluate the significance of the determined signaling pathways in the chondrogenic differentiation induced by this gel. In this study, ATDC5 cells cultured on PAMPS gel using the maintenance medium without insulin (PAMPS Culture) were compared with cells cultured on polystyrene using the differentiation medium containing insulin (PS-I Culture). The microarray analysis, Western blot analysis, and real-time PCR analysis demonstrated that the TGF-/BMP signaling pathway was significantly enhanced at Days 1, 2, and 3 in the PAMPS Culture when compared with the PS-I Culture. Inhibition of the BMP type-I receptor reduced the phosphorylation level of Smad1/5 and expression of type-2 collagen and aggrecan mRNA in the cells accompanied by a reduction in cell aggregation at Day 13 in the PAMPS Culture. The inhibition of the TGF-/BMP signaling pathway significantly inhibited the chondrogenic differentiation induced by the PAMPS gel. The present study demonstrated that synthetic PAMPS gel activates the TGF-/BMP/Smad signaling pathway in the ATDC5 cells in the absence of insulin, and that this activation plays a significant role in the chondrogenic differentiation induced by PAMPS gel. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 734-746, 2016. - Receptor activator of NF-κB ligand induces cell adhesion and integrin α2 expression via NF-κB in head and neck cancers.
Yamada T, Tsuda M, Wagatsuma T, Fujioka Y, Fujioka M, Satoh AO, Horiuchi K, Nishide S, Nanbo A, Totsuka Y, Haga H, Tanaka S, Shindoh M, Ohba Y
Scientific reports, 6, 23545, NATURE PUBLISHING GROUP, 2016年03月, [査読有り]
英語, 研究論文(学術雑誌), Cellular interactions with the extracellular matrix play critical roles in tumor progression. We previously reported that receptor activator of NF-kappa B ligand (RANKL) specifically facilitates head and neck squamous cell carcinoma (HNSCC) progression in vivo. Here, we report a novel role for RANKL in the regulation of cell adhesion. Among the major type I collagen receptors, integrin alpha 2 was significantly upregulated in RANKL-expressing cells, and its knockdown suppressed cell adhesion. The mRNA abundance of integrin alpha 2 positively correlated with that of RANKL in human HNSCC tissues. We also revealed that RANK-NF-kappa B signaling mediated integrin alpha 2 expression in an autocrine/paracrine manner. Interestingly, the amount of active integrin beta 1 on the cell surface was increased in RANKL-expressing cells through the upregulation of integrin alpha 2 and endocytosis. Moreover, the RANK-integrin alpha 2 pathway contributed to RANKL-dependent enhanced survival in a collagen gel and inhibited apoptosis in a xenograft model, demonstrating an important role for RANKL-mediated cell adhesion in three-dimensional environments. - Attenuation of ligand-induced activation of angiotensin II type 1 receptor signaling by the type 2 receptor via protein kinase C
Takayuki Inuzuka, Yoichiro Fujioka, Masumi Tsuda, Mari Fujioka, Aya O. Satoh, Kosui Horiuchi, Shinya Nishide, Asuka Nanbo, Shinya Tanaka, Yusuke Ohba
SCIENTIFIC REPORTS, 6, 21613, NATURE PUBLISHING GROUP, 2016年02月, [査読有り]
英語, 研究論文(学術雑誌), Angiotensin II (AII) type 2 receptor (AT2R) negatively regulates type 1 receptor (AT1R) signaling. However, the precise molecular mechanism of AT2R-mediated AT1R inhibition remains poorly understood. Here, we characterized the local and functional interaction of AT2R with AT1R. AT2R colocalized and formed a complex with AT1R at the plasma membrane, even in the absence of AII. Upon AII stimulation, the spatial arrangement of the complex was modulated, as confirmed by Forster resonance energy transfer (FRET) analysis, followed by AT2R internalization along with AT1R. AT2R internalization was specifically observed only in the presence of AT1R; AT2R alone could not be internalized. The AT1R-specific inhibitor losartan completely inhibited both the conformational change and the internalization of AT2R with AT1R, whereas the AT2R-specific inhibitor PD123319 partially hindered these phenomena, demonstrating that the activation of both receptors was indispensable for these effects. In addition, treatment with the protein kinase C (PKC) inhibitors inhibited the ligand-dependent accumulation of AT2R but not that of AT1R in the endosomes. A mutation in the putative phosphorylation sites of AT2R also abrogated the co-internalization of ATR2 with AT1R and the inhibitory effect of ATR2 on AT1R. These data suggest that AT2R inhibits ligand-induced AT1R signaling through the PKC-dependent pathway. - Rapid immunocytochemistry based on alternating current electric field using squash smear preparation of central nervous system tumors
Jun Moriya, Mishie Ann Tanino, Tomoko Takenami, Tomoko Endoh, Masana Urushido, Yasutaka Kato, Lei Wang, Taichi Kimura, Masumi Tsuda, Hiroshi Nishihara, Shinya Tanaka
BRAIN TUMOR PATHOLOGY, 33, 1, 13, 18, SPRINGER JAPAN KK, 2016年01月, [査読有り]
英語, 研究論文(学術雑誌), The role of intraoperative pathological diagnosis for central nervous system (CNS) tumors is crucial for neurosurgery when determining the surgical procedure. Especially, treatment of carmustine (BCNU) wafers requires a conclusive diagnosis of high-grade glioma proven by intraoperative diagnosis. Recently, we demonstrated the usefulness of rapid immunohistochemistry (R-IHC) that facilitates antigen-antibody reaction under alternative current (AC) electric field in the intraoperative diagnosis of CNS tumors; however, a higher proportion of water and lipid in the brain parenchyma sometimes leads to freezing artifacts, resulting in poor quality of frozen sections. On the other hand, squash smear preparation of CNS tumors for cytology does not affect the frozen artifacts, and the importance of smear preparation is now being re-recognized as being better than that of the tissue sections. In this study, we established the rapid immunocytochemistry (R-ICC) protocol for squash smears of CNS tumors using AC electric field that takes only 22 min, and demonstrated its usefulness for semi-quantitative Ki-67/MIB-1 labeling index and CD 20 by R-ICC for intraoperative diagnosis. R-ICC by AC electric field may become a substantial tool for compensating R-IHC and will be applied for broad antibodies in the future. - Clinicopathological study of pilomyxoid-spectrum astrocytomas: An analysis of the BRAF gene. Report of two cases
Tamio Ito, Kenichi Sato, Mitsuteru Oikawa, Hironori Sugio, Taku Asanome, Yoshimaru Ozaki, Hirohiko Nakamura, Shinya Tanaka, Masumi Tsuda, Kazuo Nagashima
Neurological Surgery, 43, 9, 825, 833, Igaku-Shoin Ltd, 2015年09月01日, [査読有り]
日本語, 研究論文(学術雑誌), In contrast to pilocytic astrocytomas (PAs), pilomyxoid astrocytomas (PMAs) demonstrate monophasic piloid cells with angiocentric distribution and a more aggressive clinical course. Recently, several reports have described combined histological features of both subtypes
accordingly, these were termed intermediate pilomyxoid tumors (IPTs). The KIAA1549-BRAF fusion gene has been found in approximately 70% of PAs, but is reportedly rare in PMAs. We describe a clinicopathological study of two patients with pilomyxoid-spectrum astrocytoma (PMSA). Case 1 was of a 29-year-old man who presented with a generalized seizure. Gadolinium-magnetic resonance imaging (Gd-MRI) demonstrated a less enhanced tumor in the left temporal lobe. Case 2 was of a 9-year-old boy who presented with headache. Gd-MRI revealed an irregularly enhanced tumor in the left cerebellum. In Case 1, the tumor showed monomorphous bipolar cells in a myxoid background and angiocentric arrangement
therefore, the diagnosis was PMA. In Case 2, part of the tumor had a myxoid, angiocentric pattern characteristic of PMA
the other part had a biphasic pattern characteristic of PA. PMA and PA were mixed in a 7:3 ratio
therefore, IPT was diagnosed. No BRAF V600E mutations were found by immunohistochemistry and sequencing in either case. Three major KIAA1549-BRAF fusion subtypes were analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) and sequencing. No fusions were found in Case 1. However, K16-B9 fusion was identified in Case 2, and this fusion was more prevalent in the PA component than in the PMA component. In summary, no BRAF V600E mutations were found in PMSAs, but KIAA1549-BRAF fusion was identified in IPT, particularly in the PA component. - Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy
Jun-ichi Furukawa, Masumi Tsuda, Kazue Okada, Taichi Kimura, Jinhua Piao, Shinya Tanaka, Yasuro Shinohara
PLOS ONE, 10, 7, e0128300, PUBLIC LIBRARY SCIENCE, 2015年07月, [査読有り]
英語, 研究論文(学術雑誌), Cancer cells frequently express glycans at different levels and/or with fundamentally different structures from those expressed by normal cells, and therefore elucidation and manipulation of these glycosylations may provide a beneficial approach to cancer therapy. However, the relationship between altered glycosylation and causal genetic alteration(s) is only partially understood. Here, we employed a unique approach that applies comprehensive glycomic analysis to a previously described multistep tumorigenesis model. Normal human astrocytes were transformed via the serial introduction of hTERT, SV40ER, HRasV12, and myrAKT, thereby mimicking human brain tumor grades I-IV. More than 160 glycans derived from three major classes of cell surface glycoconjugates (N-and O-glycans on glycoproteins, and glycosphingolipids) were quantitatively explored, and specific glycosylation patterns related to malignancy were systematically identified. The sequential introduction of hTERT, SV40ER, H-RasV12, and myrAKT led to (i) temporal expression of pauci-mannose/mono-antennary type N-glycans and GD3 (hTERT); (ii) switching from ganglio-to globo-series glycosphingolipids and the appearance of Neu5Gc (hTERT and SV40ER); (iii) temporal expression of bisecting GlcNAc residues, a2,6-sialylation, and stage-specific embryonic antigen-4, accompanied by suppression of core 2 O-glycan biosynthesis (hTERT, SV40ER and Ras); and (iv) increased expression of (neo) lacto-series glycosphingolipids and fucosylated N-glycans (hTERT, SV40ER, Ras and AKT). These sequential and transient glycomic alterations may be useful for tumor grade diagnosis and tumor prognosis, and also for the prediction of treatment response. - Tyr724 phosphorylation of ELMO1 by Src is involved in cell spreading and migration via Rac1 activation
Yoshinori Makino, Masumi Tsuda, Yusuke Ohba, Hiroshi Nishihara, Hirofumi Sawa, Kazuo Nagashima, Shinya Tanaka
CELL COMMUNICATION AND SIGNALING, 13, 35, BIOMED CENTRAL LTD, 2015年07月, [査読有り]
英語, 研究論文(学術雑誌), Background: The complex of Dock180/ELMO1 that functions as a bipartite guanine nucleotide exchange factor for Rac is essential for diverse physiological and pathological processes of cells such as cell migration, phagocytosis, and invasion of cancer cells. Among the Src-family tyrosine kinases (SFKs), it has been reported that Hck directly phosphorylates ELMO1, regulating phagocytosis by promoting activation of Rac1; however, the involvement of other SFKs in ELMO1 phosphorylation has remained unknown. Here, we identified novel tyrosine (Y) residues of ELMO1 phosphorylated by SFKs, and examined the effects on Rac1 activity, cell adhesion, spreading, and cell motility on extracellular matrix (ECM).
Results: In this study, we unveiled that Src and Fyn can induce tyrosine phosphorylation of ELMO1 in in vivo and in vitro phosphorylation assays. Mutational analyses identified both Y720 and Y724 residues of ELMO1 as Src-mediated phosphorylation sites, preferentially on Y724. Single substitution of Y724 to Phe abrogated Rac1 activation triggered by Src. To elucidate the biological function of pY724, we established NIH3T3 cells stably expressing wild-type ELMO1 or its Y724F mutant together with Dock180. Among them, Y724-deficient cells exhibited a depletion of Rac1 activity with diminished phosphorylation of ELMO1 even upon the ECM-stimulation. It is noteworthy that NIH3T3 cells with ELMO1 Y724F were strikingly defective to promote cell spreading on fibronectin-coated dish, concomitantly exhibiting immature assemblies of actin stress fibers and focal adhesions. Eventually, ELMO1 Y724F significantly impaired cell migration.
Conclusion: These results define that Src-mediated Y724 phosphorylation in ELMO1 plays a critical role for cell spreading via activation of Rac1, leading to promotion of cell migration. As the overexpression and/or hyperactivation of Src have been shown in a wide variety of human cancers, Src-mediated phosphorylation of Y724 in ELMO1 may regulate cancer cell adhesion to the ECM, invasion into surrounding tissues, and subsequent distant metastasis. - Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop.
Ryuji Matsumoto, Masumi Tsuda, Lei Wang, Nako Maishi, Takashige Abe, Taichi Kimura, Mishie Tanino, Hiroshi Nishihara, Kyoko Hida, Yusuke Ohba, Nobuo Shinohara, Katsuya Nonomura, Shinya Tanaka
Cancer science, 106, 6, 709, 17, 2015年06月, [査読有り], [国際誌]
英語, 研究論文(学術雑誌), We have previously reported that an adaptor protein CRK, including CRK-I and CRK-II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues. - HIGH ALDO-KETO REDUCTASE 1C1 EXPRESSION IN METASTATIC BLADDER CANCER CELLS ASSOCIATED WITH INVASIVE POTENTIAL AND DRUG RESISTANCE
Matsumoto Ryuji, Tsuda Masumi, Abe Takashige, Maruyama Satoru, Tsuchiya Kunihiko, Miyajima Naoto, Shinohara Nobuo, Tanaka Shinya
JOURNAL OF UROLOGY, 193, 4, E535, 2015年04月, [査読有り] - Calcium signaling mediated influenza virus entry into host cells.
Y. Fujioka, M. Tsuda, A. Nanbo, T. Hattori, J. Sasaki, T. Sasaki, T. Miyazaki, Y. Ohba
MOLECULAR BIOLOGY OF THE CELL, 25, AMER SOC CELL BIOLOGY, 2014年12月, [査読有り]
英語 - SS18-SSX-regulated miR-17 promotes tumor growth of synovial sarcoma by inhibiting p21WAF1/CIP1
Yusuke Minami, Shinji Kohsaka, Masumi Tsuda, Kazuhiro Yachi, Nobuaki Hatori, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Akio Minami, Norimasa Iwasaki, Shinya Tanaka
CANCER SCIENCE, 105, 9, 1152, 1159, WILEY-BLACKWELL, 2014年09月, [査読有り]
英語, 研究論文(学術雑誌), MicroRNA (miRNA) can function as tumor suppressors or oncogenes, and also as potential specific cancer biomarkers; however, there are few published studies on miRNA in synovial sarcomas, and their function remains unclear. We transfected the OncomiR miRNA Precursor Virus Library into synovial sarcoma Fuji cells followed by a colony formation assay to identify miRNAs to confer an aggressive tumorigenicity, and identified miR-17-5p from the large colonies. MiR-17 was found to be induced by a chimeric oncoprotein SS18-SSX specific for synovial sarcoma, and all examined cases of human synovial sarcoma expressed miR-17, even at high levels in several cases. Overexpression of miR-17 in synovial sarcoma cells, Fuji and HS-SYII, increased colony forming ability in addition to cell growth, but not cell motility and invasion. Tumor volume formed in mice in vivo was significantly increased by miR-17 overexpression with a marked increase of MIB-1 index. According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3-UTR of p21 mRNA. Indeed, p21 protein level was remarkably decreased by miR-17 overexpression in a p53-independent manner. It is noteworthy that miR-17 succeeded in suppressing doxorubicin-evoked higher expression of p21 and conferred the drug resistance. Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21. Taken together, miR-17 promotes the tumor growth of synovial sarcomas by post-transcriptional suppression of p21, which may be amenable to innovative therapeutic targeting in synovial sarcoma. - Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma
Shinji Kohsaka, Kunihiko Hinohara, Lei Wang, Tatsunori Nishimura, Masana Urushido, Kazuhiro Yachi, Masumi Tsuda, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Noriko Gotoh, Shinya Tanaka
NEURO-ONCOLOGY, 16, 7, 960, 970, OXFORD UNIV PRESS INC, 2014年07月, [査読有り]
英語, 研究論文(学術雑誌), Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target.
Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples.
Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG.
These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG-overexpressing GBM patients. - Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma
Roshan Mahabir, Mishie Tanino, Aiman Elmansuri, Lei Wang, Taichi Kimura, Tamio Itoh, Yusuke Ohba, Hiroshi Nishihara, Hiroki Shirato, Masumi Tsuda, Shinya Tanaka
NEURO-ONCOLOGY, 16, 5, 671, 685, OXFORD UNIV PRESS INC, 2014年05月, [査読有り]
英語, 研究論文(学術雑誌), Ionizing irradiation is an effective treatment for malignant glioma (MG); however, a higher rate of recurrence with more aggressive phenotypes is a vital issue. Although epithelial-mesenchymal transition (EMT) is involved in irradiation-induced cancer progression, the role for such phenotypic transition in MG remains unknown.
To investigate the mechanism of irradiation-dependent tumor progression in MG, we performed immunohistochemistry (IHC) and qRT-PCR using primary and recurrent MG specimens, MG cell lines, and primary culture cells of MG. siRNA technique was used for MG cell lines.
In 22 cases of clinically recurrent MG, the expression of the mesenchymal markers vimentin and CD44 was found to be increased by IHC. In paired identical MG of 7 patients, the expression of collagen, MMPs, and YKL-40 were also elevated in the recurrent MGs, suggesting the The Cancer Genome Atlas-based mesenchymal subtype. Among EMT regulators, sustained elevation of Snail was observed in MG cells at 21 days after irradiation. Cells exhibited an upregulation of migration, invasion, numbers of focal adhesion, and MMP-2 production, and all of these mesenchymal features were abrogated by Snail knockdown. Intriguingly, phosphorylation of ERK1/2 and GSK-3 were increased after irradiation in a Snail-dependent manner, and TGF- was elevated in both fibroblasts and macrophages but not in MG cells after irradiation. It was noteworthy that irradiated cells also expressed stemness features such as SOX2 expression and tumor-forming potential in vivo.
We here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role. - Differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma: a case report of an elderly man
Kenta Takahashi, Masumi Tsuda, Hiromi Kanno, Junichi Murata, Roshan Mahabir, Yusuke Ishida, Taichi Kimura, Mishie Tanino, Hiroshi Nishihara, Kazuo Nagashima, Shinya Tanaka
BRAIN TUMOR PATHOLOGY, 31, 2, 118, 123, SPRINGER JAPAN KK, 2014年04月, [査読有り]
英語, 研究論文(学術雑誌), Small cell glioblastoma is a histological subtype of glioblastoma with characteristic features of highly proliferative, monotonous small glial cells with high nuclear cytoplasm ratio. Morphologically, malignant lymphoma or small cell metastatic carcinoma should be carefully discriminated. Some cases are difficult to differentiate from anaplastic oligodendroglioma. In this report, we present a case of small cell glioblastoma of an elderly man. The lack of IDH1/2 mutation was confirmed by immunohistochemistry and direct sequencing. Fluorescence in situ hybridization revealed the lower rates of chromosome 1p and 19q deletion. Microsatellite analysis disclosed partial 10q alteration near the PTEN locus. Not only morphological and immunohistochemical examinations, but also cytogenetical investigations for IDH1/2 mutation, 1p/19q loss, and PTEN alteration, are strongly supportive methods for the differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma. - C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma
Futoshi Kawamata, Shigenori Homma, Hirofumi Kamachi, Takahiro Einama, Yasutaka Kato, Masumi Tsuda, Shinya Tanaka, Masahiro Maeda, Kazunori Kajino, Okio Hino, Norihiko Takahashi, Toshiya Kamiyama, Hiroshi Nishihara, Akinobu Taketomi, Satoru Todo
JOURNAL OF GASTROENTEROLOGY, 49, 1, 81, 92, SPRINGER JAPAN KK, 2014年01月, [査読有り]
英語, 研究論文(学術雑誌), Background Lymph node metastasis is a key event of colorectal cancer (CRC) progression. Mesothelin is expressed in various types of malignant tumor and associated with an unfavorable prognosis. The full-length mesothelin (Full-ERC) is cleaved by protease into membrane-bound C-ERC/mesothelin and N-ERC/mesothelin which is secreted into the blood. The aim of this study was to examine the biological role of mesothelin in CRC by clinicopathological analysis and in vitro lymphatic invasion assay.
Methods Ninety-one cases of CRC specimens were immunohistochemically examined and the localization of mesothelin in luminal membrane and/or cytoplasm was also evaluated. Lymphatic invasion assay was also performed using the human CRC cell line, WiDr, which was transfected with Full-, N- and C-ERC/mesothelin expression plasmids (Full-WiDr, N-WiDr and C-WiDr).
Results Immunohistochemically, "luminal membrane positive" of mesothelin was identified in 37.4 %, and correlated with lymphatic permeation and lymph node metastasis, but not with patients' prognosis. Interestingly, among the patients with lymph node metastasis (N = 38), "luminal membrane positive" of mesothelin significantly correlated with unfavorable patients' outcome. In addition, lymphatic invasion assay revealed that Full-WiDr and C-WiDr more significantly invaded human lymphatic endothelial cells than the Mock-WiDr (P < 0.01).
Conclusion The luminal membrane expression of mesothelin was associated with unfavorable prognosis of CRC patients with lymph nodemetastasis. Moreover, this is the first report to prove the biological function of C-ERC/mesothelin associated with lymphatic invasion of cancer in vitro. - NS1-binding protein abrogates the elevation of cell viability by the influenza A virus NS1 protein in association with CRKL
Masaya Miyazaki, Hiroshi Nishihara, Hideki Hasegawa, Masato Tashiro, Lei Wang, Taichi Kimura, Mishie Tanino, Masumi Tsuda, Shinya Tanaka
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 441, 4, 953, 957, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013年11月, [査読有り]
英語, 研究論文(学術雑誌), The influenza A virus non-structural protein 1 (NS1) is a multifunctional virulence factor consisting of an RNA binding domain and several Src-homology (SH) 2 and SH3 binding motifs, which promotes virus replication in the host cell and helps to evade antiviral immunity. NS1 modulates general host cell physiology in association with various cellular molecules including NS1-binding protein (NS1-BP) and signaling adapter protein CRK-like (CRKL), while the physiological role of NS1-BP during influenza A virus infection especially in association with NS1 remains unclear. In this study, we analyzed the intracellular association of NS1-BP, NS1 and CRKL to elucidate the physiological roles of these molecules in the host cell. In HEK293T cells, enforced expression of NS1 of A/Beijing (H1N1) and A/Indonesia (H5N1) significantly induced excessive phosphorylation of ERR and elevated cell viability, while the over-expression of NS1-BP and the abrogation of CRKL using siRNA abolished such survival effect of NS1. The pull-down assay using GST-fusion CRKL revealed the formation of intracellular complexes of NS1-BP, NS1 and CRKL. In addition, we identified that the N-terminus SH3 domain of CRKL was essential for binding to NS1-BP using GST-fusion CRKL-truncate mutants. This is the first report to elucidate the novel function of NS1-BP collaborating with viral protein NS1 in modulation of host cell physiology. In addition, an alternative role of adaptor protein CRKL in association with NS1 and NS1-BP during influenza A virus infection is demonstrated. (C) 2013 Elsevier Inc. All rights reserved. - A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection
Yoichiro Fujioka, Masumi Tsuda, Asuka Nanbo, Tomoe Hattori, Junko Sasaki, Takehiko Sasaki, Tadaaki Miyazaki, Yusuke Ohba
NATURE COMMUNICATIONS, 4, 2763, NATURE PUBLISHING GROUP, 2013年11月, [査読有り]
英語, 研究論文(学術雑誌), Various viruses enter host cells via endocytosis, but the molecular mechanisms underlying the specific internalization pathways remain unclear. Here we show that influenza A viruses (IAVs) enter cells via redundant pathways of clathrin-mediated and clathrin-independent endocytosis, with intracellular Ca2+ having a central role in regulation of both pathways by activating a signalling axis comprising RhoA, Rho-kinase, phosphatidylinositol 4-phosphate 5-kinase (PIP5K) and phospholipase C (PLC). IAV infection induces oscillations in the cytosolic Ca2+ concentration of host cells, the prevention of which markedly attenuates virus internalization and infection. The small GTPase RhoA is found both to function downstream of the virus-induced Ca2+ response and itself to induce Ca2+ oscillations in a manner dependent on Rho-kinase and subsequent PIP5K-PLC signalling. This signalling circuit regulates both clathrin-mediated and clathrin-independent endocytosis during virus infection and seems to constitute a key mechanism for regulation of IAV internalization and infection. - Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma
Hiromi Kanno, Hiroshi Nishihara, Lei Wang, Sayaka Yuzawa, Hiroyuki Kobayashi, Masumi Tsuda, Taichi Kimura, Mishie Tanino, Shunsuke Terasaka, Shinya Tanaka
NEURO-ONCOLOGY, 15, 7, 853, 864, OXFORD UNIV PRESS INC, 2013年07月, [査読有り]
英語, 研究論文(学術雑誌), Background. CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients' poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression.
Methods. First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163-overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo.
Results. Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163-overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor-derived granulocyte colony-stimulating factor (G-CSF) production, which was confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay.
Conclusions. To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma. - Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein
Rachel Kobos, Makoto Nagai, Masumi Tsuda, Man Yee Merl, Tsuyoshi Saito, Marick Lae, Qianxing Mo, Adam Olshen, Steven Lianoglou, Christina Leslie, Irina Ostrovnaya, Christophe Antczak, Hakim Djaballah, Marc Ladanyi
JOURNAL OF PATHOLOGY, 229, 5, 743, 754, WILEY-BLACKWELL, 2013年04月, [査読有り]
英語, 研究論文(学術雑誌), Oncogenic rearrangements of the TFE3 transcription factor gene are found in two distinct human cancers. These include ASPSCR1TFE3 in all cases of alveolar soft part sarcoma (ASPS) and ASPSCR1TFE3, PRCC-TFE3, SFPQ-TFE3 and others in a subset of paediatric and adult RCCs. Here we examined the functional properties of the ASPSCR1TFE3 fusion oncoprotein, defined its target promoters on a genome-wide basis and performed a high-throughput RNA interference screen to identify which of its transcriptional targets contribute to cancer cell proliferation. We first confirmed that ASPSCR1TFE3 has a predominantly nuclear localization and functions as a stronger transactivator than native TFE3. Genome-wide location analysis performed on the FU-UR-1 cell line, which expresses endogenous ASPSCR1TFE3, identified 2193 genes bound by ASPSCR1TFE3. Integration of these data with expression profiles of ASPS tumour samples and inducible cell lines expressing ASPSCR1TFE3 defined a subset of 332 genes as putative up-regulated direct targets of ASPSCR1TFE3, including MET (a previously known target gene) and 64 genes as down-regulated targets of ASPSCR1TFE3. As validation of this approach to identify genuine ASPSCR1TFE3 target genes, two up-regulated genes bound by ASPSCR1TFE3, CYP17A1 and UPP1, were shown by multiple lines of evidence to be direct, endogenous targets of transactivation by ASPSCR1TFE3. As the results indicated that ASPSCR1TFE3 functions predominantly as a strong transcriptional activator, we hypothesized that a subset of its up-regulated direct targets mediate its oncogenic properties. We therefore chose 130 of these up-regulated direct target genes to study in high-throughput RNAi screens, using FU-UR-1 cells. In addition to MET, we provide evidence that 11 other ASPSCR1TFE3 target genes contribute to the growth of ASPSCR1TFE3-positive cells. Our data suggest new therapeutic possibilities for cancers driven by TFE3 fusions. More generally, this work establishes a combined integrated genomics/functional genomics strategy to dissect the biology of oncogenic, chimeric transcription factors. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. - 脳腫瘍の現代病理学 BRAF異常とグリオーマ
田中 伸哉, 谷野 美智枝, 津田 真寿美, 石田 雄介, 木村 太一, 西原 広史, 長嶋 和郎
日本病理学会会誌, 102, 1, 203, 203, (一社)日本病理学会, 2013年04月
日本語 - Relationship between Methyl CpG Binding Protein 2 and JC Viral Proteins
Kenta Takahashi, Yasuko Orba, Taichi Kimura, Lei Wang, Shinji Kohsaka, Masumi Tsuda, Mishie Tanino, Hiroshi Nishihara, Kazuo Nagashima, Hirofumi Sawa, Shinya Tanaka
JAPANESE JOURNAL OF INFECTIOUS DISEASES, 66, 2, 126, 132, NATL INST INFECTIOUS DISEASES, 2013年03月, [査読有り]
英語, 研究論文(学術雑誌), JC virus (JCV) is a causative agent of progressive multifocal leukoencephalopathy (PML). Methyl CpG binding protein 2 (MeCP2) is a transcriptional control nuclear protein that is abundantly expressed in neurons. We previously observed that the MeCP2 protein is expressed in JCV large T antigen (TAg)-expressing glial cells in PML brains. To investigate the relationship between MeCP2 and JCV TAg, we examined the promoter activity and mRNA and protein expression levels of MeCP2 in JCV TAg-expressing cells. We found that JCV TAg enhances the promoter activity of MeCP2, but does not enhance the mRNA and protein levels of MeCP2. These results suggest that post-transcriptional mechanisms may play a role in MeCP2 expression. - Fluorescent protein-based biosensors and their clinical applications
Yusuke Ohba, Yoichiro Fujioka, Shigeyuki Nakada, Masumi Tsuda
Progress in Molecular Biology and Translational Science, 113, 313, 348, 2013年, [査読有り]
英語, 研究論文(学術雑誌), Green fluorescent protein and its relatives have shed their light on a wide range of biological problems. To date, with a color palette consisting of fluorescent proteins with different spectra, researchers can "paint" living cells as they desire. Moreover, sophisticated biosensors engineered to contain single or multiple fluorescent proteins, including FRET-based biosensors, spatiotemporally unveil molecular mechanisms underlying physiological processes. Although such molecules have contributed considerably to basic research, their abilities to be used in applied life sciences have yet to be fully explored. Here, we review the molecular bases of fluorescent proteins and fluorescent protein-based biosensors and focus on approaches aimed at applying such proteins to the clinic. © 2013 Elsevier Inc. - Simultaneous inhibition of Src and Aurora kinases by SU6656 induces therapeutic synergy in human synovial sarcoma growth, invasion and angiogenesis in vivo
Ryuta Arai, Masumi Tsuda, Takuya Watanabe, Toyoyuki Ose, Chikashi Obuse, Katsumi Maenaka, Akio Minami, Yusuke Ohba
EUROPEAN JOURNAL OF CANCER, 48, 15, 2417, 2430, ELSEVIER SCI LTD, 2012年10月, [査読有り]
英語, 研究論文(学術雑誌), Synovial sarcoma is an obstinate, high-grade malignancy because of its modest responses to radiotherapy and chemotherapy; the identification of effective therapeutics for this sarcoma is therefore necessary. Inhibition of Src family kinases (SFKs) suppresses the proliferation of synovial sarcoma cells in vitro, as we have previously reported. In this study, to validate the efficacy of Src inhibition in vivo, we employed SU6656, which was originally identified as a specific SFK inhibitor. SU6656 treatment significantly impaired the growth of established, existing tumours formed by synovial sarcoma cells in mice. Tumour cell invasion into the surrounding tissues was also abolished by SU6656. It is noteworthy that SU6656 but not PP2 induced a defect in cleavage furrow formation during cytokinesis, resulting in G2/M accumulation and subsequent apoptosis. Intriguingly, SU6656 abrogated the catalytic activities of Aurora kinases and led to the down-regulation of phosphorylated histone H3 coincidently with p53 accumulation, as did the Aurora kinase inhibitor VX-680. Structural comparison indicated an extensive similarity between the catalytic domains of SFKs and Aurora kinases. The structural analysis also revealed the potential binding mode of SU6656 to the ATP-binding cleft of Aurora B via four hydrogen bonds. SU6656 prevented angiogenesis within the tumours by attenuating vascular endothelial growth factor (VEGF) production by tumour cells and the subsequent chemotaxis of endothelial cells; these effects were the result of the inhibition of SFKs but not Aurora kinases. Based on these results, we hereby report a novel property of SU6656 as a dual inhibitor of SFKs and Aurora kinases, the suppression of both of which effectively abrogates tumour development and the progression of synovial sarcoma in vivo. (C) 2011 Elsevier Ltd. All rights reserved. - Biosensors for BCR-ABL activity and their application to cancer
Yusuke Ohba, Stephanie Darmanin, Tatsuaki Mizutani, Masumi Tsuda, Takeshi Kondo
Biosensors and Cancer, 268, 283, CRC Press, 2012年01月01日
英語, 論文集(書籍)内論文, The emergence of imatinib mesylate
designed to inhibit the causativeprotein of chronic myeloid leukemia-BCR-ABL, has radicallyinnovated the treatment of this disease, making it now controllable byoral drugs. However resistance and intolerance are still of concern in asubstantial number of patients. A recently developed biosensor, whichutilizes the major BCR-ABL substrate CrkL, green fluorescent proteintechnology, and the principle of Förster resonance energy transfer, to overcome these issues in chronic myeloid leukemia treatment isintroduced here. This novel diagnostic method for the measurementof BCR-ABL activity has a higher sensitivity than that of establishedtechniques. It can be used as an accurate gauge of BCR-ABL kinaseactivity in small numbers of living cells, and is a useful tool for thedetection of minor drug-resistant populations, as well as the predictionof the clinical course after drug treatment and future onset of drugresistance using patient cells. In consideration of its quick and practicalnature, this method is potentially a promising tool for the predictionof both current and future therapeutic responses in individual patientswith chronic myeloid leukemia, which will surely be beneficial for bothpatients and clinicians. Moreover, the biosensor now provides a newwindow for the application of fluorescent proteins in the practical sceneof clinical medicine, whereas to date, their contributions have only beenlimited to basic research fields. - Visualization of intracellular signaling and its application to assessment of response to molecular target drugs
Yusuke Ohba, Masumi Tsuda
Seikagaku, 84, 5, 359, 365, 5, 2012年, [査読有り]
日本語 - Roles for Crk in Cancer Metastasis and Invasion
Masumi Tsuda, Shinya Tanaka
Genes and Cancer, 3, 5-6, 334, 340, 5-6, 2012年, [査読有り]
英語, 研究論文(学術雑誌), The Crk family of adaptors is implicated in regulating various biological and pathological processes such as cell proliferation, adhesion, migration, invasion, phagocytosis, and survival. A large number of studies have shown that Crk plays an important role in aggressive and malignant behaviors of human cancers. In immunohistochemical analyses and gene-expression profiles, enhanced expression of Crk has been identified in adenocarcinomas of lung, breast, and stomach and in sarcomas and glioma. Overexpression of Crk in tumor cells induces the prominent tyrosine phosphorylations of scaffolding molecules such as p130Cas and paxillin through Src family tyrosine kinases and stimulates the activation loop of intracellular signalling, ultimately contributing to the increased motility and aggressive potential of cancer cells. Crk proteins thus are not simply conduits for intracellular signal transduction but also can control the amplitude of signalling. This review summarizes the significance of Crk and its mediated signaling assemblies, particularly in regulating tumor metastasis and invasion, and discusses the possibilities that they are potential cancer therapeutic targets. © The Author(s) 2012. - FRETバイオセンサーによるCML細胞のチロシンキナーゼ阻害薬感受性試験~臨床検体での有用性の検討
近藤健, 金安顕子, 盛暁生, 入江達朗, 津田真寿美, 森岡正信, 今村雅寛, 大場雄介
臨床血液, 52, 9, 1133, 2011年09月30日
日本語 - [Visualization of cellular signaling by fluorescent proteins].
Ohba Y, Tsuda M
Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 138, 1, 13, 17, 1, 2011年07月, [査読有り]
日本語, 下村脩博士によって,<I>Aequorea victoria</I> の発光器官から緑色蛍光タンパク質GFP(green fluorescent protein)が発見され,1992年にそのcDNAが単離されて以来,生細胞イメージングは生物学研究の必須ツールになっている.GFPはcDNAの細胞導入のみで,生理的環境下での目的タンパク質の局在や局在変化を可視化し,種々のカラーバリアントが入手可能な現在では複数のタンパク質の挙動の同時観察も可能である.また,フェルスター共鳴エネルギー移動(FRET: Förster resonance energy transfer)や蛍光タンパク質再構成法(BiFC: bimolecular fluorescence complementation)等の技術を用いることで,個々のタンパク質の局在や動態のみならずタンパク質の質的変化,つまりタンパク質間相互作用・構造変化等の時間的・空間的な変化の解析も可能である.これらの手法は細胞内シグナル伝達のダイナミクスを解析するために,最も適したツールと言っても過言ではない.本稿では,蛍光イメージングの基礎や応用例の紹介と各実験系が持つ得失を比較し,それぞれの実験系が何を可視化するのに適しているかを議論したい. - RANKL Expression Specifically Observed in Vivo Promotes Epithelial Mesenchymal Transition and Tumor Progression
Tamaki Yamada, Masumi Tsuda, Tomomi Takahashi, Yasunori Totsuka, Masanobu Shindoh, Yusuke Ohba
AMERICAN JOURNAL OF PATHOLOGY, 178, 6, 2845, 2856, ELSEVIER SCIENCE INC, 2011年06月, [査読有り]
英語, 研究論文(学術雑誌), Recent findings have focused attention on the molecular consequences of the microenvironment in tumor progression, but events occurring in cancer cells themselves in response to their ambient conditions remain obscure. Here, we identify receptor activator of nuclear factor kappa B ligand (RANKL) as a microenvironment-specific factor essential for tumorigenesis in vivo, using head and neck squamous cell carcinoma (HNSCC) as a model. In human HNSCC tissues, RANKL is abundantly expressed, and its expression level correlates with the histological grade of differentiation. RANKL levels are significantly higher in poorly differentiated SCCs than in well or moderately differentiated SCCs. In contrast, all HNSCC cell lines tested displayed extremely low RANKL expression; however, RANKL is efficiently up-regulated when these cell lines are inoculated in the head and neck region of mice. RANKL expression is restored in a microenvironment-specific manner, and cannot be observed when the cells are inoculated in the hindlimbs. Forced expression of RANKL compensates for tumor growth in the hindlimb milieu, promotes epithelial mesenchymal transition, and induces tumor angiogenesis, in a manner independent of vascular endothelial growth factor (VEGF). These results implicate RANKL expression causatively in tumor growth and progression in HNSCC in vivo. RANKL may provide a novel functional marker for biological malignancy and a therapeutic target based on the specific nature of the microenvironment. (Am J Pathol 2011, 178:2845-2854. DOI: 10.1016/j.ajpath.2011.02.003) - The Ras-PI3K Signaling Pathway Is Involved in Clathrin-Independent Endocytosis and the Internalization of Influenza Viruses
Yoichiro Fujioka, Masumi Tsuda, Tomoe Hattori, Junko Sasaki, Takehiko Sasaki, Tadaaki Miyazaki, Yusuke Ohba
PLOS ONE, 6, 1, e16324, PUBLIC LIBRARY SCIENCE, 2011年01月, [査読有り]
英語, 研究論文(学術雑誌), Background: Influenza virus infection causes highly contagious, severe respiratory disorders and gives rise to thousands of deaths every year; however, the efficacy of currently approved defense strategies, including vaccines and neuraminidase inhibitors, is limited because the virus frequently acquires resistance via antigen drift and reassortment. It is therefore important to establish a novel, effective therapeutic strategy that is effective irrespective of viral subtype.
Methodology/Principal Findings: Here, we identify the Ras-phosphoinositide 3-kinase (PI3K) signaling pathway as a host-cell regulatory mechanism for influenza virus entry. The binding of Ras to PI3K is specifically involved in clathrinin-dependent endocytosis, endosomal maturation, and intracellular transport of viruses, which result in decreased infectious efficacy of different subtypes of influenza viruses in cells lacking the Ras-PI3K interaction. Moreover, influenza virus infection indeed triggered Ras activation and subsequent PI3K activation in early endosomes.
Conclusions/Significance: Taken together, these results demonstrate that the Ras-PI3K signaling axis acts as a host-oriented mechanism for viral internalization. Given that virus incorporation is a process conserved among virus subtypes and species, this signaling pathway may provide a target for potent, well-tolerated prophylactics and therapeutics against a broad range of viruses. - A Novel FRET-Based Biosensor for the Measurement of BCR-ABL Activity and Its Response to Drugs in Living Cells
Tatsuaki Mizutani, Takeshi Kondo, Stephanie Darmanin, Masumi Tsuda, Shinya Tanaka, Minoru Tobiume, Masahiro Asaka, Yusuke Ohba
CLINICAL CANCER RESEARCH, 16, 15, 3964, 3975, AMER ASSOC CANCER RESEARCH, 2010年08月, [査読有り]
英語, 研究論文(学術雑誌), Purpose: To develop a novel diagnostic method for the assessment of drug efficacy in chronic myeloid leukemia (CML) patients individually, we generated a biosensor that enables the evaluation of BCR-ABL kinase activity in living cells using the principle of fluorescence resonance energy transfer (FRET).
Experimental Design: To develop FRET-based biosensors, we used CrkL, the most characteristic substrate of BCR-ABL, and designed a protein in which CrkL is sandwiched between Venus, a variant of YFP, and enhanced cyan fluorescent protein, so that CrkL intramolecular binding of the SH2 domain to phosphorylated tyrosine (Y207) increases FRET efficiency. After evaluation of the properties of this biosensor by comparison with established methods including Western blotting and flow cytometry, BCR-ABL activity and its response to drugs were examined in CML patient cells.
Results: After optimization, we obtained a biosensor that possesses higher sensitivity than that of established techniques with respect to measuring BCR-ABL activity and its suppression by imatinib. Thanks to its high sensitivity, this biosensor accurately gauges BCR-ABL activity in relatively small cell numbers and can also detect <1% minor drug-resistant populations within heterogeneous ones. We also noticed that this method enabled us to predict future onset of drug resistance as well as to monitor the disease status during imatinib therapy, using patient cells.
Conclusion: In consideration of its quick and practical nature, this method is potentially a promising tool for the prediction of both current and future therapeutic responses in individual CML patients, which will be surely beneficial for both patients and clinicians. Clin Cancer Res; 16(15); 3964-75. (C) 2010 AACR. - Visualization of Ras-PI3K interaction in the endosome using BiFC
Kaori Tsutsumi, Yoichiro Fujioka, Masumi Tsuda, Hideaki Kawaguchi, Yusuke Ohba
CELLULAR SIGNALLING, 21, 11, 1672, 1679, ELSEVIER SCIENCE INC, 2009年11月, [査読有り]
英語, 研究論文(学術雑誌), Recent studies indicate the importance of spatiotemporal regulation in the diversity and specificity of intracellular signaling. Here, we show that Ras-PI3K signaling plays an important role in the local regulation of phosphatidylinositol metabolism in the endosome through live-cell imaging by using a bimolecular fluorescence complementation technique, in which molecular interaction is indicated by fluorescence emission. Using several possible combinations of Ras and the Ras-binding domain, we identified an optimal set of probe molecules that yielded the most significant increase in fluorescence intensity between the active and inactive forms of Ras. This combination revealed that, among the Ras effectors tested, phosphatidy-linositol 3-kinase (PI3K) was specifically implicated in signaling in the endosome. We also found that full length PI3K was recruited to the endosome in EGF- and Ras-dependent manners, which appears to be essential for the activation of PI3K in this compartment. Taken together, these findings demonstrate that the spatiotemporal regulation of Ras-PI3K signaling may dictate the activation of PI3K and subsequent downstream signaling in the endosome. (C) 2009 Elsevier Inc. All rights reserved. - Adaptor Protein Crk Induces Src-Dependent Activation of p38 MAPK in Regulation of Synovial Sarcoma Cell Proliferation
Takuya Watanabe, Masumi Tsuda, Shinya Tanaka, Yusuke Ohba, Hideaki Kawaguchi, Tokifumi Majima, Hirofumi Sawa, Akio Minami
MOLECULAR CANCER RESEARCH, 7, 9, 1582, 1592, AMER ASSOC CANCER RESEARCH, 2009年09月, [査読有り]
英語, 研究論文(学術雑誌), The adaptor protein Crk mediates intracellular signaling related to cell motility and proliferation and is implicated in human tumorigenesis. The role of Crk in the growth of human sarcoma has remained unclear, however. The present study shows that Crk-induced activation of Src and subsequent signaling by p38 mitogen-activated protein kinase (MAPK) contribute to the enhanced proliferation of human synovial sarcoma cells. Depletion of Crk by RNA interference markedly inhibited proliferation of the synovial sarcoma cell lines HS-SYII, SYO-1, and Fuji as well as prevented anchorage-independent growth. Conversely, reconstitution with CrkII by authentic small interfering RNA-resistant Crk gene restored proliferation in Crk-silenced SYO-1 cells. Crk-depleted synovial sarcoma cells manifested enhanced transcriptional activity and expression of the p16(INK4A) gene, resulting in their accumulation in G, phase of the cell cycle. In response to hepatocyte growth factor stimulation, Crk prominently induced the tyrosine phosphorylation of Grb2-associated binder 1 through activation of Src and focal adhesion kinase, and the Src family kinase inhibitor PP2 almost completely inhibited the proliferation of SYO-1 cells. Crk also induced the phosphorylation of p38 MAPK, and SB203580, a p38 MAPK-specific inhibitor, increased expression of p16(INK4A) gene in SYO-1 cells. Furthermore, SB203580 or depletion of p38 MAPK by small interfering RNA suppressed both the phosphorylation of Akt triggered by hepatocyte growth factor and the proliferation of SYO-1 cells. These results suggest that Crk promotes proliferation of human synovial sarcoma cells through activation of Src and its downstream signaling by a novel p38 MAPK-Akt pathway, with these signaling molecules providing potent new targets for molecular therapeutics. (Mol Cancer Res 2009;7(9):1582-92) - Human synovial sarcoma proto-oncogene Syt is essential for early embryonic development through the regulation of cell migration
Taichi Kimura, Mieko Sakai, Kouichi Tabu, Lei Wang, Ryosuke Tsunematsu, Masumi Tsuda, Hirofumi Sawa, Kazuo Nagashima, Hiroshi Nishihara, Shigetsugu Hatakeyama, Keiko Nakayama, Marc Ladanyi, Shinya Tanaka, Keiichi I. Nakayama
LABORATORY INVESTIGATION, 89, 6, 645, 656, NATURE PUBLISHING GROUP, 2009年06月, [査読有り]
英語, 研究論文(学術雑誌), SYT-SSX protein, resulted from chromosomal translocation, causes synovial sarcoma, which is a malignant tumor accounting for 10% of soft tissue sarcoma. However, biological functions of SYT (synovial sarcoma translocation), also known as SS18, are largely unclear, whereas it has been proven that Syt-null mice die at early stages of embryonic development. Here, we generated Syt-deficient mice and confirmed the reported phenotypes, including growth retardation, open neural tube and haplo-insufficient lethality, and therefore, there is no doubt that Syt is essential for embryonic development. However, placental defects, described in the earlier report, were rarely seen in our mice and we frequently observed cardiac defect in Syt-deficient mice. As the mechanisms responsible for embryonic lethality seem to be complicate, we performed additional experiments. By using primary cultured embryonic fibroblasts, we showed that Syt(-/-) MEFs deregulate actin organization and suppressed cell migration. These observations suggest that Syt may contribute to the signaling pathway important for various cellular functions in vivo and in vitro, and we propose that Syt-deficient MEFs would be a powerful means to understand the biological roles of SYT in vitro. Laboratory Investigation (2009) 89, 645-656; doi:10.1038/labinvest.2009.25; published online 30 March 2009 - Crk adaptor protein-induced phosphorylation of Gab1 on tyrosine 307 via Src is important for organization of focal adhesions and enhanced cell migration
Takuya Watanabe, Masumi Tsuda, Yoshinori Makino, Tassos Konstantinou, Hiroshi Nishihara, Tokifumi Majima, Akio Minami, Stephan M. Feller, Shinya Tanaka
CELL RESEARCH, 19, 5, 638, 650, NATURE PUBLISHING GROUP, 2009年05月, [査読有り]
英語, 研究論文(学術雑誌), Upon growth factor stimulation, the scaffold protein, Gab1, is tyrosine phosphorylated and subsequently the adaptor protein, Crk, transmits signals from Gab1. We have previously shown that Crk overexpression, which is detectable in various human cancers, induces tyrosine phosphorylation of Gab1 without extracellular stimuli. In the present study, the underlying mechanisms were further investigated. Mutational analyses of CrkII demonstrated that the SH2 domain, but not the SH3(N) or the regulatory Y221 residue of CrkII, is critical for the induction of Gab1-Y307 phosphorylation. SH2 mutation of CrkII also decreased the interaction with Gab1. In GST pull-down assay, Crk-SH2 bound to wild-type Gab1, whereas Crk-SH3(N) interacted with the Gab1 mutant, which lacks the clustered tyrosine region (residues 242-410). Tyrosine phosphorylation of Gab1 was induced by all Crk family proteins, but not other SH2-containing signalling adaptors. Src-family kinase inhibitor, PP2, abrogates Crk-induced tyrosine phosphorylations of Gab1. Y307 phosphorylation was undetectable in fibroblasts lacking Src, Yes, and Fyn, even upon overexpression of Crk, whereas cells lacking only Yes and Fyn still contained Gab1 with phosphorylated Y307. Furthermore, Crk induced the phosphorylation of Src-Y416; accordingly the interaction between Crk and Csk was increased. The Gab1-Y307F mutant failed to localize near the plasma membrane even upon HGF stimulation and decreased cell migration. Moreover, Gab1-Y307F disturbed the localization of Crk, FAK, and paxillin, which are the typical components of focal adhesions. Taken together, these results indicate that Crk facilitates tyrosine phosphorylation of Gab1-Y307 through Src, contributing to the organization of focal adhesions and enhanced cell migration, thereby possibly promoting human cancer development. - Transcription factor 8 activates R-Ras to regulate angiogenesis
Takayuki Inuzuka, Masumi Tsuda, Hideaki Kawaguchi, Yusuke Ohba
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 379, 2, 510, 513, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2009年02月, [査読有り]
英語, 研究論文(学術雑誌), We have recently reported that transcription factor 8 (TCF8) negatively regulates pathological angiogenesis by regulating endothelial invasiveness by acting as a transcriptional attenuator of matrix metalloproteinase 1. TCF8 also modulates cell-matrix and cell-cell adhesion; however molecular mechanism of this TCF8 function remains obscure. Here, we provide evidence that TCF8 activates R-Ras, another class of angiogenic regulator, to suppress angiogenesis by a mechanism other than a transcriptional attenuator. Tube formation by human umbilical vein endothelial cells (HUVECs) facilitated by TCF8 suppression was significantly inhibited by the expression of constitutive active mutant of R-Ras. When we examined the mRNA expression levels of R-Ras regulators, no significant changes were observed to explain the R-Ras activation by TCF8. Interestingly, we found that TCF8 bound to CalDAG-GEFIII, an R-Ras activator, in the cytosol, indicating that TCF8 emanates signaling for R-Ras activation from cytosol to regulate angiogenesis negatively. (C) 2008 Elsevier Inc. All rights reserved. - Integral Role of Transcription Factor 8 in the Negative Regulation of Tumor Angiogenesis
Takayuki Inuzuka, Masumi Tsuda, Shinya Tanaka, Hideaki Kawaguchi, Yujiro Higashi, Yusuke Ohba
CANCER RESEARCH, 69, 4, 1678, 1684, AMER ASSOC CANCER RESEARCH, 2009年02月, [査読有り]
英語, 研究論文(学術雑誌), Angiogenesis is involved in various physiologic and pathological conditions, including tumor growth, and is tightly regulated by the orchestration of proangiogenic and antiangiogenic factors. Inhibition of vascular endothelial growth factor (VEGF), the best-established antiangiogenic treatment in cancer, has shown some effectiveness; however, the identification of novel regulators, whose function is independent of VEGF, is required to achieve better outcomes. Here, we show that transcription factor 8 (TCF8) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator. Furthermore, TCF8 is specifically expressed in the endothelium of tumor vessels. 1cf8-heterozygous knockout mice are more permissive than wildtype mice to the formation of tumor blood vessels in s.c. implanted melanoma, which seems to contribute to the more aggressive growth and the lung metastases of the tumor in mutant mice. Suppression of TCF8 facilitates angiogenesis in both in vitro and ex vivo models, and displays comprehensive cellular phenotypes, including enhanced cell invasion, impaired cell adhesion, and increased cell monolayer permeability due to, at least partly, MMPI overexpression, attenuation of focal adhesion formation, and insufficient VE-cadherin recruitment, respectively. Taken together, our findings define a novel, integral role for TCF8 in the regulation of pathologic angiogenesis, and propose TCF8 as a target for therapeutic intervention in cancer. [Cancer Res 2009;69(4):1678-84] - Increased Motility and Invasiveness in Tumor Cells That Survive 10 Gy Irradiation
Kaori Tsutsumi, Masumi Tsuda, Natsuka Yazawa, Hirotaka Nakamura, Seiichiro Ishihara, Hisashi Haga, Motoaki Yasuda, Rie Yamazaki, Hiroki Shirato, Hideaki Kawaguchi, Takeshi Nishioka, Yusuke Ohba
CELL STRUCTURE AND FUNCTION, 34, 2, 89, 96, JAPAN SOC CELL BIOLOGY, 2009年, [査読有り]
英語, 研究論文(学術雑誌), Radiotherapy is an important noninvasive treatment for many types of cancer. However, it has been reported that the proliferative, invasive, and metastatic capacities of tumor cells can be increased in the repopulated tumors that survive radiotherapy. We have previously established a radiation-surviving cell model for the human non-small cell lung cancer cell line H1299 by harvesting relic cells 14 days after irradiation (IR cells). Here, we report that cell invasion, cell migration, and cell adhesion are enhanced in these surviving cancer cells. The mRNA expression levels of matrix metalloproteinases (MMPs), including mmp1, mmp2, and mmp9, were upregulated in IR cells compared with parental cells. A gelatin zymogram, wound healing assay, and invasion assay showed increased MMP activity, cell motility, and invasiveness in IR cells, respectively. Moreover, IR cells adhered more tightly to collagen-coated dishes than parental cells. Consistently, paxillin, phosphorylated FAK, integrin beta 1, and vinculin were strongly localized at focal adhesions in IR cells, as visualized by immunofluorescence. In this report, we identify molecules responsible for the malignant properties of tumor cells that survive irradiation. These molecules may be important therapeutic targets for the control of repopulated tumors after radiotherapy. - Adaptor protein Crk is implicated in mucus formation in mucinous epithelial ovarian cancer (mEOC) cells MCAS
Xu Dong-mei, Linghu Hua, Masumi Tsuda, Shinya Tanaka, Kazuo Nagashima
CHINESE JOURNAL OF CANCER RESEARCH, 20, 2, 121, 125, SPRINGER, 2008年06月, [査読有り]
英語, 研究論文(学術雑誌), Objective: The mucus production is an indicator for the histological grade of mucinous epithelial ovarian cancer (mEOC). In our previous study, Crk expression was targeted in the human ovarian mucinous adenocarcinoma cell line MCAS through RNA interference, resulting in the establishment of Crk knock down cells. These cells exhibited decreased tumorigenic potential both in vitro and in vivo. The purpose of this study was to investigate if there is any change in the capability of forming mucus in these Crk knock down cells. Methods: Cytoplasmic periodic acid Schiff (PAS) staining and particle excluding assay were conducted to assess the mucus formation within and around cells, respectively. Additionally, the amount of mucus formed in tumor lumps from nude mice model was measured following HE and PAS staining. Results: The increased mucus production in Crk knockdown mEOC cells (MCAS) was manifested by increased number of enlarged cells filled with vacuoles-like mucus observed by phase-contrast microscope and cytoplasmic PAS staining; and enhanced mucus secretion was represented by the assembly of pericellular matrix in particle excluding assay and increased mucus area in tumor lumps from nude mice models. Conclusion: The course of carcinogenesis in mEOC is associated with the altered pattern of mucus production and secretion. The adaptor protein Crk is implicated in both pathways. - PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling
Tamaki Yamada, Masumi Tsuda, Yusuke Ohba, Hideaki Kawaguchi, Yasunori Totsuka, Masanobu Shindoh
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 368, 3, 575, 581, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2008年04月, [査読有り]
英語, 研究論文(学術雑誌), Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer. (c) 2008 Elsevier Inc. All rights reserved. - Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4
Lei Wang, Kouichi Tabu, Taichi Kimura, Masumi Tsuda, Hua Linghu, Mishie Tanino, Sadao Kaneko, Hiroshi Nishihara, Shinya Tanaka
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 362, 4, 976, 981, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2007年11月, [査読有り]
英語, 研究論文(学術雑誌), Signaling adaptor protein Crk has been shown to be involved in pathogenesis of human cancers including brain tumor where Crk was reported to be overexpressed. In this study, we addressed whether Crk is indispensable for malignant phenotype of brain tumor. In 20 surgical specimens of glioma, mRNA of both CrkI and CrkII was found to be elevated in malignant tumor. To define a precise role of Crk, we have established Crk-knockdown cell lines of glioblastoma KMG4 by siRNA, and early phase of cell adhesion to laminin was found to be suppressed. Wound healing assay revealed the decreased cell motility in Crk knockdown cells, and suppression of both anchorage-dependent and -independent growth were demonstrated in these cells. Furthermore, in vivo tumor forming potential was also markedly suppressed. These results suggest that Crk is required for early attachment to laminin, cell motility, and growth of glioblastoma cell line KMG4. (C) 2007 Elsevier Inc. All rights reserved. - TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition
Masumi Tsuda, Ian J. Davis, Pedram Argani, Neerav Shukla, Gael G. McGill, Makoto Nagai, Tsuyoshi Saito, Marick Lae, David E. Fisher, Marc Ladanyi
CANCER RESEARCH, 67, 3, 919, 929, AMER ASSOC CANCER RESEARCH, 2007年02月, [査読有り]
英語, 研究論文(学術雑誌), Specific chromosomal translocations encoding chimeric transcription factors are considered to play crucial oncogenic roles in a variety of human cancers but the fusion proteins themselves seldom represent suitable therapeutic targets. Oncogenic TFE3 fusion proteins define a subset of pediatric renal adenocarcinomas and one fusion (ASPL-TFE3) is also characteristic of alveolar soft part sarcoma (ASPS). By expression profiling, we identified the MET receptor tyrosine kinase gene as significantly overexpressed in ASPS relative to four other types of primitive sarcomas. We therefore examined MET as a direct transcriptional target of ASPL=TFE3. ASPL TFE3 binds to the MET promoter and strongly activates it. Likewise, PSF-TFE3 and NONO=TFE3 also bind this promoter. Induction of MET by ASPL-TFE3 results in strong MET autophosphorylation and activation of downstream signaling in the presence of hepatocyte growth factor (HGF). In cancer cell lines containing endogenous TFE3 fusion proteins, inhibiting MET by BNA interference or by the inhibitor PHA665752 abolishes HGF-dependent MET activation, causing decreased cell growth and loss of HGF-dependent phenotypes. MET is thus a potential therapeutic target in these cancers. Aberrant transcriptional up-regulation of MET by oncogenic TFE3 fusion proteins represents another mechanism by which certain cancers become dependent on MET signaling. The identification of kinase signaling pathways transcriptionally up-regulated by oncogenic fusion proteins may reveal more accessible therapeutic targets in this class of human cancers. - Adaptor molecule Crk is required for sustained phosphorylation of Grb2-associated binder 1 and hepatocyte growth factor-induced cell motility of human synovial sarcoma cell lines
Takuya Watanabe, Masumi Tsuda, Yoshinori Makino, Shin Ichihara, Hirofumi Sawa, Akio Minami, Naoki Mochizuki, Kazuo Nagashima, Shinya Tanaka
MOLECULAR CANCER RESEARCH, 4, 7, 499, 510, AMER ASSOC CANCER RESEARCH, 2006年07月, [査読有り]
英語, 研究論文(学術雑誌), Activation of the c-Met receptor tyrosine kinase through its ligand, hepatocyte growth factor (HGF), promotes mitogenic, motogenic, and morphogenic cellular responses. Aberrant HGF/c-Met signaling has been strongly implicated in tumor cell invasion and metastasis. Both HGF and its receptor c-Met have been shown to be overexpressed in human synovial sarcoma, which often metastasizes to the lung; however, little is known about HGF-mediated biological effects in this sarcoma. Here, we provide evidence that Crk adaptor protein is required for the sustained phosphorylation of c-Met-docking protein Grb2-associated binder 1 (Gab1) in response to HGF, leading to the enhanced cell motility of human synovial sarcoma cell lines SY0-1, HS-SY-II, and Fuji. HGF stimulation induced the sustained phosphorylation on Y307 of Gab1 where Crk was recruited. Crk knockdown by RNA interference disturbed this HGF-induced tyrosine phosphorylation of Gab1. By mutational analysis, we identified that Src homology 2 domain of Crk is indispensable for the induction of the phosphorylation on multiple Tyr-X-X-Pro motifs containing Y307 in Gab1. HGF remarkably stimulated cell motility and scattering of synovial sarcoma cell lines, consistent with the prominent activation of Rac1, extreme filopodia formation, and membrane ruffling. Importantly, the elimination of Crk in these cells induced the disorganization of actin cytoskeleton and complete abolishment of HGF-mediated Rac1 activation and cell motility. Time-lapse microscopic analysis revealed the significant attenuation in scattering of Crk knockdown cells following HGF treatment. Furthermore, the depletion of Crk remarkably inhibited the tumor formation and its invasive growth in vivo. These results suggest that the sustained phosphorylation of Gab1 through Crk in response to HGF contributes to the prominent activation of Rac1 leading to enhanced cell motility, scattering, and cell invasion, which may support the crucial role of Crk in the aggressiveness of human synovial sarcoma. - Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS
H Linghu, M Tsuda, Y Makino, M Sakai, T Watanabe, S Ichihara, H Sawa, K Nagashima, N Mochizuki, S Tanaka
ONCOGENE, 25, 25, 3547, 3556, NATURE PUBLISHING GROUP, 2006年06月
英語, 研究論文(学術雑誌), Signaling adaptor protein Crk regulates cell motility and growth through its targets Dock180 and C3G, those are the guanine-nucleotide exchange factors (GEFs) for small GTPases Rac and Rap, respectively. Recently, overexpression of Crk has been reported in various human cancers. To de. ne the role for Crk in human cancer cells, Crk expression was targeted in the human ovarian cancer cell line MCAS through RNA interference, resulting in the establishment of three Crk knockdown cell lines. These cell lines exhibited disorganized actin fibers, reduced number of focal adhesions, and abolishment of lamellipodia formation. Decreased Rac activity was demonstrated by pull-down assay and FRET-based time-lapse microscopy, in association with suppression of both motility and invasion by phagokinetic track assay and transwell assay in these cells. Furthermore, Crk knockdown cells exhibited slow growth rates in culture and suppressed anchorage-dependent growth in soft agar. Tumor forming potential in nude mice was attenuated, and intraperitoneal dissemination was not observed when Crk knockdown cells were injected into the peritoneal cavity. These results suggest that the Crk is a key component of focal adhesion and involved in cell growth, invasion, and dissemination of human ovarian cancer cell line MCAS. - A novel function of OLIG2 to suppress human glial tumor cell growth via p27(Kip1) transactivation
K Tabu, A Ohnishi, Y Sunden, T Suzuki, M Tsuda, S Tanaka, T Sakai, K Nagashima, H Sawa
JOURNAL OF CELL SCIENCE, 119, 7, 1433, 1441, COMPANY OF BIOLOGISTS LTD, 2006年04月, [査読有り]
英語, 研究論文(学術雑誌), The basic helix-loop-helix transcription factor OLIG2 is specifically expressed in cells of the oligodendrocyte lineage. It is also expressed in various tumors originating from glial cells; however, the expression of OLIG2 is rare or weak in glioblastomas, the most malignant gliomas. The role of OLIG2 in glioma remains unclear. To investigate the function of OLIG2 in glial tumor cells, we have established a glioblastoma cell line, U12-1, in which the expression of OLIG2 is induced by the Tet-off system. Induction of OLIG2 resulted in suppression of both the proliferation and anchorage-independent growth of U12-1. It also resulted in an increase in the expression of p27(Kip1). A luciferase assay revealed that the CTF site of the p27(Kip1) gene promoter was essential for OLIG2-dependent activation of p27(Kip1) gene transcription. Electrophoretic mobility shift assays confirmed that a nuclear extract of OLIG2-expressing U12-1 cells contained a protein complex that binds to the CTF site of the p27(Kip1) gene promoter. Furthermore, siRNA against p27(Kip1) rescued the OLIG2-mediated growth and DNA synthesis inhibition of U12-1 cells. These results indicate that OLIG2 suppresses the proliferation of U12-1 and that this effect is mediated by transactivation of the p27(Kip1) gene, and low expression of OLIG2 may be related to the malignant behavior of human glioblastoma. - Elmo1 inhibits ubiquitylation of Dock180
Y Makino, M Tsuda, S Ichihara, T Watanabe, M Sakai, H Sawa, K Nagashima, S Hatakeyama, S Tanaka
JOURNAL OF CELL SCIENCE, 119, 5, 923, 932, COMPANY OF BIOLOGISTS LTD, 2006年03月, [査読有り]
英語, 研究論文(学術雑誌), Dock180, a member of the CDM family of proteins, plays roles in biological processes such as phagocytosis and motility through its association with the signalling adaptor protein Crk. Recently, the complex formation between Dock180 and Elmo1 was reported to function as a bipartite guanine nucleotide exchange factor for Rac. In this study, we demonstrated that the amount of Dock180 increased when Elmo1 was co-expressed. Dock180 was found to be ubiquitylated and Dock180 protein levels could be augmented by treatment with proteasome inhibitor. The ubiquitylation of Dock180 was enhanced by epidermal growth factor (EGF), Crk and adhesion-dependent signals. Furthermore, Elmo1 inhibited labiquitylation of Dock180, resulting in the increase in Dock180 levels. The Elmo1 mutant Delta 531, which encompasses amino acids required for Dock180 binding, preserved the inhibitory effects on ubiquitylation of Dock180. Upon EGF stimulation, both Dock180 and ubiquitin were demonstrated to translocate to the cell periphery by immunofluorescence, and we found ubiquitylation of Dock180 and its inhibition by Elmo1 to occur in cellular membrane fractions by in vivo ubiquitylation assay. These data suggest that Dock180 is ubiquitylated on the plasma membrane, and also that Elmo1 functions as an inhibitor of ubiquitylation of Dock180. Therefore, an ubiquitin-proteasome-dependent protein degradation mechanism might contribute to the local activation of Rac on the plasma membrane. - 高齢者の生理学的特徴--高齢者がん患者の臨床検査からみた機能評価 (特集 高齢者がんの特徴と治療法の新展開)
津田 真寿美, 川口 秀明
癌の臨床, 52, 12, 721, 730, 篠原出版新社, 2006年
日本語 - Induction of p21(WAF1/CIP1) by human synovial sarcoma-associated chimeric oncoprotein SYT-SSX1
M Tsuda, T Watanabe, T Seki, T Kimura, H Sawa, A Minami, T Akagi, K Isobe, K Nagashima, S Tanaka
ONCOGENE, 24, 54, 7984, 7990, NATURE PUBLISHING GROUP, 2005年12月, [査読有り]
英語, 研究論文(学術雑誌), Oncogenic protein provokes cell cycle arrest termed premature senescence. In this process Ras has been known to induce cyclin-dependent kinase inhibitor (CKI) p16(INK4A) in primary fibroblasts. Here, we present a novel finding that human chimeric oncoprotein SYT-SSX1 induces CKI p21(WAF1/CIP1) (p21) for suppression of cell growth. In human synovial sarcoma cell lines, the expression levels of p21 were high and the transcriptional activity of the p21 gene promoter was significantly elevated. The transient expression of SYT- SSX1-induced activation of the p21 gene promoter in human diploid fibroblasts. The N-terminus deletion form of SYT-SSX1, which failed to bind to hBRM one of the chromatin remodeling factors, preserved the p21 induction ability. This effect of SYT-SSX1 was similar in extent in both wild-type and p53-deficient HCT116 cell lines. Furthermore, the introduction of mutation in Sp1/Sp3 binding sites of the p21 gene promoter abolished the SYT-SSX1-induced transcriptional activity of its promoter. In SW13 cells, the stable expression of SYT-SSX1 suppressed cell growth in culture. These results suggest that SYT-SSX1 is able to induce p21 in a manner independent on hBRM and p53 but dependent on Sp1/Sp3. - Crk associates with ERM proteins and promotes cell motility toward hyaluronic acid
M Tsuda, Y Makino, T Iwahara, H Nishihara, H Sawa, K Nagashima, H Hanafusa, S Tanaka
JOURNAL OF BIOLOGICAL CHEMISTRY, 279, 45, 46843, 46850, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2004年11月, [査読有り]
英語, 研究論文(学術雑誌), Cell migration is a well organized process regulated by the extracellular matrix-mediated cytoskeletal reorganization. The signaling adaptor protein Crk has been shown to regulate cell motility, but its precise role is still under investigation. Herein, we report that Crk associates with ERM family proteins ( including ezrin, radixin, and moesin), activates RhoA, and promotes cell motility toward hyaluronic acid. The binding of Crk with ERMs was demonstrated both by transient and stable protein expression systems in 293T cells and 3Y1 cells, and it was shown that v-Crk translocated the phosphorylated form of ERMs to microvilli in 3Y1 cells by immunofluorescence and immunoelectron microscopy. This v-Crk-dependent formation of microvilli was suppressed by inhibitors of Rho-associated kinase, and the activity of RhoA was elevated by coexpression of c-Crk-II and ERMs in 3Y1 cells. In concert with the activation of RhoA by Crk, Crk was found to associate with Rho-GDI, which has been shown to bind to ERMs. Furthermore, upon hyaluronic acid treatment, coexpression of c-Crk-II and ERMs enhanced cell motility, whereas the sole expression of c-Crk-II or either of the ERMs decreased the motility of 3Y1 cells. These results suggest that Crk may be involved in regulation of cell motility by a hyaluronic acid-dependent mechanism through an association with ERMs. - Nuclear entry mechanism of the human polyomavirus JC virus-like particle - Role of importins and the nuclear pore complex
QM Qu, H Sawa, T Suzuki, S Semba, C Henmi, Y Okada, M Tsuda, S Tanaka, WJ Atwood, K Nagashima
JOURNAL OF BIOLOGICAL CHEMISTRY, 279, 26, 27735, 27742, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2004年06月, [査読有り]
英語, 研究論文(学術雑誌), JC virus (JCV) belongs to the polyomavirus family of double-stranded DNA viruses and causes progressive multifocal leukoencephalopathy in humans. Although transport of virions to the nucleus is an important step in JCV infection, the mechanism of this process has remained unclear. The outer shell of the JCV virion comprises the major capsid protein VP1, which possesses a putative nuclear localization signal (NLS), and virus-like particles (VLPs) consisting of recombinant VP1 exhibit a virion-like structure and physiological functions ( cellular attachment and intracytoplasmic trafficking) similar to those of JCV virions. We have now investigated the mechanism of nuclear transport of JCV with the use of VLPs. Wild-type VLPs (wtVLPs) entered the nucleus of most HeLa or SVG cells. The virion structure of VLPs was preserved during transport to the nucleus as revealed by confocal microscopy of cells inoculated with fluorescein isothiocyanate-labeled wtVLPs containing packaged Cy3. The nuclear transport of wtVLPs in digitonin-permeabilized cells was dependent on the addition of importins alpha and beta and was prevented by wheat germ agglutinin or by antibodies to the nuclear pore complex. The nuclear entry of VLPs composed of VP1 with a mutated NLS was greatly inhibited, compared with that of wtVLPs, in both intact and permeabilized cells. Unlike wtVLPs, the mutant VLPs did not bind to importins alpha or beta. Limited proteolysis analysis revealed that the NLS of VP1 was exposed on the surface of wtVLPs. These results suggest that JCV VLPs bind to cellular importins via the NLS of VP1 and are transported into the nucleus through the nuclear pore complex. - Expression of the oligodendroglial lineage-associated markers Olig1 and Olig2 in different types of human gliomas
A Ohnishi, H Sawa, M Tsuda, Y Sawamura, T Itoh, Y Iwasaki, K Nagashima
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 62, 10, 1052, 1059, AMER ASSN NEUROPATHOLOGISTS INC, 2003年10月, [査読有り]
英語, 研究論文(学術雑誌), Because a specific group of oligodendrogliomas is susceptible to adjuvant therapy, it is important to elucidate the biological characteristics of these tumors. In situ hybridization analyses have revealed that Olig genes are expressed in oligodendroglial lineage cells and are highly expressed in oligodendrogliomas. To clarify whether OLIG is a tumor-specific marker for oligodendrogliomas, we have investigated the expression of Olig transcripts by semiquantitative RT-PCR assay and OLIG2 protein with a new antibody in a variety of glial tumors. The semiquantitative RT-PCR revealed that high levels of expression of Olig1 and Olig2 mRNAs were present in anaplastic oligodendrogliomas and anaplastic astrocytomas, while expression of these mRNAs in grade IV glioblastomas was lower than in grade II and grade III gliomas (p < 0.01). Immunohistochemical analyses demonstrated that the mean immunopositive proportion of OLIG2 was 82% in anaplastic oligodendrogliomas but only 34% in anaplastic astrocytomas. Therefore, although OLIG2 expression was detected in a range of gliomas not specific for oligodendrogliomas, the expression level in anaplastic oligodendrogliomas was more uniform and intense than that in other glial tumors. In conclusion, combining Olig mRNA expression and immunohistochemistry of OLIG2 enables oligodendrogliomas to be distinguished from glioblastomas and other astrocytic glial tumors. - キメラ遺伝子と病理診断 滑膜肉腫の臨床病理学特徴とSYT‐SSXキメラ遺伝子産物による細胞癌化のメカニズム
田中伸哉, 津田真寿美, 平賀博明, 三浪明男, 長嶋和郎
病理と臨床, 21, 6, 593, 603, 2003年06月01日
日本語 - An association of Bcl-2 phosphorylation and Bax localization with their functions after hyperthermia and paclitaxel treatment
AE Salah-Eldin, S Inoue, SE Tsukamoto, H Aoi, M Tsuda
INTERNATIONAL JOURNAL OF CANCER, 103, 1, 53, 60, WILEY-LISS, 2003年01月, [査読有り]
英語, 研究論文(学術雑誌), Apoptosis is induced by many kinds of therapy-related inducers, such as hyperthermia and chemotherapeutic agents. However, differences in apoptotic pathways between these inducers remain unclear, although knowing the differences is important to map out a therapeutic strategy. Therefore, we focused on the localization and phosphorylation of Bcl-2 and Bax, key mediators of the apoptotic pathway, after hyperthermia and paclitaxel treatment of PC-10 squamous cell carcinoma cells that excessively expressed Bcl-2 and Bax in the cytoplasm. Paclitaxel treatment markedly induced qualitative changes in Bcl-2, whereas hyperthermia did only quantitative changes in Bax. The levels of Bax increased gradually with the duration of hyperthermia, whereas Bcl-2 levels slightly decreased. On the other hand, paclitaxel treatment induced dose- and time-dependent phosphorylation of Bcl-2. Interestingly, phosphorylated Bcl-2 was observed in the specific subcellular sites, mitochondria- and lysosome-rich fractions. Both treatments disturbed the heterodimerization of Bax with Bcl-2. Hyperthermia, but not paclitaxel treatment, induced a gradual Bax translocation from the cytoplasm to the nucleus. Although both treatments induced a prominent cell cycle disturbance in the G(2)M phase, paclitaxel treatment induced typical apoptosis, and hyperthermia hardly induced apoptosis. Our results suggest that the subcellular redistribution of Bax and the phosphorylation of Bcl-2 depend on the type of apoptosis inducers, such as hyperthermia and paclitaxel, and Bcl-2 has a central role in the decision of apoptotic outcome. Our data may afford new insights in apoptosis from the aspect of an association of Bcl-2 phosphorylation with intracellular Bax localization. (C) 2002 Wiley-Liss, Inc. - DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines
H Nishihara, M Maeda, A Oda, M Tsuda, H Sawa, K Nagashima, S Tanaka
BLOOD, 100, 12, 3968, 3974, AMER SOC HEMATOLOGY, 2002年12月, [査読有り]
英語, 研究論文(学術雑誌), The CDM (ced-5 of Caenorhabditis elegans, DOCK180 [downstream of Crk with molecular weight of 180 kDa] of humans, and myoblast city of Drosophila melanogaster) family of proteins has been shown to play a pivotal role in the integrin-mediated signaling pathway under the regulation of an adaptor molecule c-CT10- related kinase II (c-Crk-II) in adherent cells. Recently, hematopoietic cell-specific CDM protein DOCK2 has been shown to be indispensable for lymphocyte migration. However, the regulatory mechanism for DOCK2 is still unknown because DOCK2 lacks a c-Crk-II binding consensus motif. In this study, we demonstrated that DOCK2 bound to CrkL, which is present exclusively in hematopoietic cells both in vivo and in vitro, and we also found that 2 separate regions of DOCK2 contributed to its binding to Src homology 3 (SH3) domain of CrkL. Colocalization of DOCK2 with Crk-like (CrkL) and F-actin was shown by immunocytochemical analysis with the use of Jurkat cells. We also found that CrkL-induced activation of small guanine triphosphatase (GTPase) Rac1 was significantly inhibited by the DOCK2-dCS mutant in 293T cells. Furthermore, the association of DOCK2 and Vav, the guanine-nucleotide exchanging factor (GEF) for Rac1, was demonstrated in Jurkat cells. Finally, the stable expression of DOCK2-dCS mutant in Jurkat cells was shown to reduce cell attachment. These data suggest the presence of a novel protein complex of CrkL, DOCK2, and Vav to regulate Rac1 in leukemia cell lines. (C) 2002 by The American Society of Hematology. - DOCK2 mediates T cell receptor-induced activation of Rac2 and IL-2 transcription
H Nishihara, M Maeda, M Tsuda, Y Makino, H Sawa, K Nagashima, S Tanaka
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 296, 3, 716, 720, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2002年08月, [査読有り]
英語, 研究論文(学術雑誌), DOCK2, a CDM family protein exclusively found in hematopoietic cells, has been shown to play a role in lymphocyte migration by the regulation of actin cytoskeleton. Although DOCK2 has been shown to induce the activation of Rac1, the regulatory mechanism of Rac2, which is a hematopoietic cell-specific small GTPase, is still unknown. In this study, we examined the role of DOCK2 in the activation of Rac2 in hematopoietic cells. DOCK2 was found to associate with the zeta subunit of the CD3 complex of T cell receptors in Jurkat cells and to activate forced expressed Rac2 in 293T cells. In addition, the stable expression of DOCK2 in Jurkat cells exhibited the elevated activity of endogenous Rac2. Furthermore, the transcriptional activity of interleukin-2 (IL-2) was enhanced in DOCK2-expressing Jurkat cells and the dominant negative form of Rac2 suppressed its elevated IL-2 promoter activity. These results suggest that DOCK2 mediates TCR-dependent activation of Rac2, leading to the regulation of IL-2 promoter activity in T cells. (C) 2002 Elsevier Science (USA). All rights reserved. - Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers
H Nishihara, S Tanaka, M Tsuda, S Oikawa, M Maeda, M Shimizu, H Shinomiya, A Tanigami, H Sawa, K Nagashima
CANCER LETTERS, 180, 1, 55, 61, ELSEVIER SCI IRELAND LTD, 2002年06月, [査読有り]
英語, 研究論文(学術雑誌), Crk is a signaling adaptor protein which is mostly composed of SH2 and SH3 domains. and has been shown to play a pivotal role in cell proliferation. differentiation, and migration. Because Crk was originally isolated as an avian sarcoma virus CT10 encoding oncoprotein v-Crk. we examined a potential role for c-Crk in the carcinogenesis of human cancers. First, to analyze gene mutations of c-Crk, we isolated a human bacterial artificial chromosome clone containing Crk genome and exon/intron structures, However, polymerase chain reaction-single strand conformation polymorphism methods failed to show any genomic mutations in the Crk exon which could be related to carcinogenesis. Second, immunohistochemical analysis of c-Crk-II demonstrated that the levels of c-Crk-II were significantly elevated in most of the tumors, particularly in the colon and lung cancers. Furthermore, immunoblot analysis using human lung cancer cell lines revealed that the expression levels of c-Crk-II were correlated to growth rates of L cells. The elevated expression levels of c-Crk-II might be related to the development of human cancers. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. - Signaling adaptor protein v-Crk activates Rho and regulates cell motility in 3Y1 rat fibroblast cell line
M Tsuda, S Tanaka, H Sawa, H Hanafusa, K Nagashima
CELL GROWTH & DIFFERENTIATION, 13, 3, 131, 139, AMER ASSOC CANCER RESEARCH, 2002年03月, [査読有り]
英語, 研究論文(学術雑誌), The adaptor protein Crk has been reported to associate with focal adhesions and is thought to be involved in integrin-mediated signaling pathway. However, the precise mechanism of Crk-dependent regulation of cytoskeleton still remains under investigation. In this study, we have established a v-Crk-inducible cell line in rat fibroblasts 3Y1 cells and found that v-Crk activated Rho and induced actin stress fiber formation. In addition to the induction of tyrosine-phosphorylation of p130(Cas) and paxillin, we demonstrated that v-Crk induced threonine-phosphorylated bands sized at 72/78 kDa found specifically in 3Y1 cells. Both of the inhibitors of Rho and Rho-associated kinase, C3 and Y27632, respectively, inhibited these v-Crk-induced biochemical effects. Although v-Crk-induced cells exhibited a decrease of cell motility, integrin stimulation recovered the suppression of motility. Furthermore, v-Crk enhanced motility in chemotactic assay toward fibronectin with additional activation of Rho and the increase of levels of CD44 cleavage. These results suggest that v-Crk activated Rho and induced actin stress fiber formation and CD44 cleavage leading to the regulation of cell motility. - Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha
M Nagai, S Tanaka, M Tsuda, S Endo, H Kato, H Sonobe, A Minami, H Hiraga, H Nishihara, H Sawa, K Nagashima
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 98, 7, 3843, 3848, NATL ACAD SCIENCES, 2001年03月, [査読有り]
英語, 研究論文(学術雑誌), Human synovial sarcoma has been shown to exclusively harbor the chromosomal translocation t(X;18) that produces the chimeric gene SYT-SSX. However, the role of SYT-SSX in cellular transformation remains unclear. In this study, we have established 3Y1 rat fibroblast cell lines that constitutively express SYT, SSX1, and SYT-SSX1 and found that SYT-SSX1 promoted growth rate in culture, anchorage-independent growth in soft agar, and tumor formation in nude mice. Deletion of the N-terminal 181 amino acids of SYT-SSX1 caused loss of its transforming activity. Furthermore, association of SYT-SSX1 with the chromatin remodeling factor hBRM/hSNF2 alpha, which regulates transcription, was demonstrated in both SYT-SSX1-expressing 3Y1 cells and in the human synovial sarcoma cell line HS-SY-II. The binding region between the two molecules was shown to reside within the N-terminal 181 amino acids stretch (aa 1-181) of SYT-SSX1 and 50 amino acids (aa 156-205) of hBRM/hSNF2 alpha and we found that the overexpression of this binding region of hBRM/hSNF2 alpha significantly suppressed the anchorage-independent growth of SYT-SSX1-expressing 3Y1 cells. To analyze the transcriptional regulation by SYT-SSX1, we established conditional expression system of SYT-SSX1 and examined the gene expression profiles. The down-regulation of potential tumor suppressor DCC was observed among 1,176 genes analyzed by microarray analysis, and semi-quantitative reverse transcription-PCR confirmed this finding. These data clearly demonstrate transforming activity of human oncogene SYT-SSX1 and also involvement of chromatin remodeling factor hBRM/hSNF2 alpha in human cancer. - Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2
Nagai, M, Tanaka, S, Tsuda, M, Endo, S, Kato, H, Sonobe, H, Minami , A, Hiraga, H, Yamawaki, S, Nishihara, H, Sawa, H, Nagashima, K
Proc.Natl.Acad.Sci.USA, 98, 7, 3843, 3848, 2001年 - Abnormal intracellular localization of Bax with a normal membrane anchor domain in human lung cancer cell lines
A Salah-eldin, S Inoue, M Tsuda, A Matsuura
JAPANESE JOURNAL OF CANCER RESEARCH, 91, 12, 1269, 1277, BUSINESS CENTER ACADEMIC SOCIETIES JAPAN, 2000年12月, [査読有り]
英語, 研究論文(学術雑誌), Proapoptotic Bax is a member of the Bcl-2 family proteins, which have a key role in regulating programmed cell death. The intracellular localization and redistribution of Bax are important in promoting apoptosis. Bax contains a BH3 domain heterodimerizing with Bcl-2 and a hydrophobic transmembrane segment to be inserted in specified organelle membranes. In this study, Bcl-2 showed cytoplasmic localization in all of ten human lung cancer cell lines tested. Interestingly, Bax was localized in the nucleus in 7 cell lines, although Bax lacks nuclear import signals. This may allow cancer cells to escape from apoptosis. Why pax is able to exist in the nucleus is still unclear. We hypothesized that mutation in the BH3 domain and/or transmembrane segment of Bax possibly causes intracellular Bax distribution. We analyzed the sequence of the bax gene in these cell lines and found only a silent point mutation at codon 184 (TCG-->TCA) in the transmembrane segment in all cell lines. This finding indicates that changes in cellular localization of Bax in lung cancer cell lines do not depend on bax mutation and that Bax is possibly translocated into the nucleus without any mutation. This is the first report showing that Bax with the normal amino acid sequence can be localized in the nucleus in established lung cancer cell lines without any treatment of the cells. - Nuclear translocation and increased expression of bax and disturbance in cell cycle progression without prominent apoptosis induced by hyperthermia
Michiru Nishita, Shoichi Inoue, Masumi Tsuda, Chie Tateda, Toshiyuki Miyashita
Experimental Cell Research, 244, 1, 357, 366, Academic Press Inc., 1998年10月10日, [査読有り]
英語, 研究論文(学術雑誌), Effects of hyperthermia at 42.5°C for 6 h on cell survival, cell cycle progression, and the localization and expression levels of Bcl-2 and Bax, as well as the association between Bcl-2 and Bax in human lung cancer cells were investigated. Untreated human lung cancer cells, though immortalized, expressed Bax unlike peripheral lymphocytes with low Bax expression. Bcl-2 was localized only in the cytoplasm in all the cell lines tested, whereas Bax was localized in the cytoplasm and/or nucleus
(1) only in the nucleus in three cell lines, (2) either in the nucleus or the cytoplasm in three cell lines, (3) in both the nucleus and the cytoplasm in one cell line, and (4) only in the cytoplasm in three cell lines. Of 10 cell lines examined, 6 had a low sensitivity to hyperthermia with a viability of 50% or more, and four cell lines had a high sensitivity to hyperthermia with a viability of less than 50% regardless of cell type. In cell lines highly sensitive to hyperthermia, Bax was localized in the nucleus. Hyperthermia increased the cellular level of Bax, but not Bcl-2, and reduced the association between Bcl-2 and Bax expression in PC-10 cells. Although the Bax level increased, hyperthermia induced only mild apoptosis and caused prominent cell cycle disturbance, especially in the S and G2M phases. Thus, hyperthermia at 42.5°C for 6 h had cytostatic effect as well as caused mild apoptosis. Interestingly, during 3 h of hyperthermia, Bax translocated from the cytoplasm to the nucleus, whereas Bcl-2 remained in the cytoplasm. These results raise the possibility that Bax may lose its function as the inducer of apoptosis by translocating into the nucleus or have an unknown role in the nucleus.
その他活動・業績
- Artificial Intelligence Predicts the Genetic Information of The Integrated Diagnosis of Brain Tumors
Yusuke Ishida, Masumi Tsuda, Jun Suzuka, Lei Wang, Satoshi Tanikawa, Hirokazu Sugino, Shinya Tanaka, MODERN PATHOLOGY, 32, 2019年03月
NATURE PUBLISHING GROUP, 英語, 研究発表ペーパー・要旨(国際会議) - Artificial Intelligence Predicts the Genetic Information of The Integrated Diagnosis of Brain Tumors
Yusuke Ishida, Masumi Tsuda, Jun Suzuka, Lei Wang, Satoshi Tanikawa, Hirokazu Sugino, Shinya Tanaka, LABORATORY INVESTIGATION, 99, 2019年03月
NATURE PUBLISHING GROUP, 英語, 研究発表ペーパー・要旨(国際会議) - A case of cauda equina primary extramedullary plasmacytoma
Yoshitaka Oda, Hirokazu Sugino, Izumi Koyanagi, Tanikawa Satoshi, Yuusuke Ishida, Masumi Tsuda, Shinya Tanaka, BRAIN PATHOLOGY, 29, 165, 165, 2019年02月
WILEY, 英語, 研究発表ペーパー・要旨(国際会議) - Development of bipolar charged hydrogel for neuronal tissue engineering
Satoshi Tanikawa, Shingo Semba, Lei Wang, Mishie Tanino, Yusuke Ishida, Hirokazu Sugino, Jun Suzuka, Masumi Tsuda, Shinya Tanaka, BRAIN PATHOLOGY, 29, 109, 109, 2019年02月
WILEY, 英語, 研究発表ペーパー・要旨(国際会議) - A case of spinal rosette-forming glioneuronal tumor
Mishie Tanino, Shuji Hamauchi, Hirokazu Sugino, Masumi Tsuda, Hidehiro Takei, Shinya Tanaka, BRAIN PATHOLOGY, 29, 160, 160, 2019年02月
WILEY, 英語, 研究発表ペーパー・要旨(国際会議) - 「首下がり」症候群を伴う筋萎縮性側索硬化症の初期段階における剖検所見
Tanikawa Satoshi, Tanino Mishie, Wang Lei, Ishikawa Marin, Miyazaki Masaya, Tsuda Masumi, Tsuda Masumi, Tsuda Masumi, Orba Yasuko, Sawa Hirofumi, Matoba Kotarou, Nakamura Nishio, Nagashima Kazuo, Hall William W., Tanaka Shinya, Tanaka Shinya, Tanaka Shinya, Neuropathology (Web), 39, 5, 2019年 - IDH1 Mutation Enhances Radiation Sensitivity by Regulating EMT and Apoptotic Pathway in Malignant Glioma
Mishie A. Tanino, Arisa Kitazaki, Mei Kuzasa, Hirokazu Sugino, Yusuke Ishida, Lei Wang, Masumi Tsuda, Shinya Tanaka, MODERN PATHOLOGY, 31, 667, 667, 2018年03月
NATURE PUBLISHING GROUP, 英語, 研究発表ペーパー・要旨(国際会議) - IDH1 Mutation Enhances Radiation Sensitivity by Regulating EMT and Apoptotic Pathway in Malignant Glioma
Mishie A. Tanino, Arisa Kitazaki, Mei Kuzasa, Hirokazu Sugino, Yusuke Ishida, Lei Wang, Masumi Tsuda, Shinya Tanaka, LABORATORY INVESTIGATION, 98, 667, 667, 2018年03月
NATURE PUBLISHING GROUP, 英語, 研究発表ペーパー・要旨(国際会議) - 低分化胃癌におけるSox10発現の臨床病理学的検討
石川 麻倫, 西原 広史, 林 秀幸, 木村 太一, 石田 雄介, 王 磊, 津田 真寿美, 谷野 美智枝, 坂本 直哉, 田中 伸哉, 日本消化器病学会雑誌, 115, 臨増総会, A375, A375, 2018年03月
(一財)日本消化器病学会, 日本語 - IDH1 mutation contributes to apoptosis after multi-fractionated irradiation in malignant glioma
Arisa Kitazaki, Mishie Tanino, Mei Kuzasa, Hirokazu Sugino, Lei Wang, Yusuke Ishida, Shingo Semba, Masumi Tsuda, Kaori Igarashi, Tomoyoshi Soga, Shinya Tanaka, CANCER SCIENCE, 109, 1130, 1130, 2018年01月
WILEY, 英語, 研究発表ペーパー・要旨(国際会議) - Expression of OTUB1 in human malignant mesothelioma
Mei Kuzasa, Mishie Tanino, Arisa Kitazaki, Hirokazu Sugino, Yusuke Ishida, Lei Wang, Masumi Tsuda, Akira Takasawa, Hiroshi Hirano, Shinya Tanaka, CANCER SCIENCE, 109, 1109, 1109, 2018年01月
WILEY, 英語, 研究発表ペーパー・要旨(国際会議) - Aanalysis of relationship between BRAF V600E mutation and expression for p16 in pleomorphic xanthoastrocytoma
Mishie A. Tanino, Hiroshi Nanjo, Masumi Tsuda, Hirokazu Sugino, Rei Wang, Yusuke Ishida, Shinya Tanaka, CANCER SCIENCE, 109, 1127, 1127, 2018年01月
WILEY, 英語, 研究発表ペーパー・要旨(国際会議) - 骨形成に再利用される合成HAp系インプラントの同位体顕微鏡観察
野々山貴行, 鈴木裕貴, 木山竜二, WANG Lei, 津田真寿美, 安田和則, 田中伸哉, 永田康祐, 藤田龍介, 坂本直哉, 圦本尚義, GONG Jian Ping, 日本セラミックス協会秋季シンポジウム講演予稿集(CD-ROM), 31st, 2018年 - 低分化胃癌におけるSox10発現の臨床病理学的検討
石川麻倫, 石川麻倫, 西原広史, 林秀幸, 木村太一, 石田雄介, 王磊, 津田真寿美, 谷野美智枝, 坂本直哉, 田中伸哉, 日本消化器病学会雑誌(Web), 115, 2018年 - アダプター分子CRKはエクソソームのErbB2を制御し、膀胱癌の増殖・転移を亢進する
津田 真寿美, 吉田 一彦, 松本 隆児, 近藤 恒徳, 篠原 信雄, 田中 伸哉, 日本癌学会総会記事, 76回, E, 1059, 2017年09月
日本癌学会, 英語 - miR-23aによる膠芽腫の浸潤能亢進分子メカニズムの解明
津田 真寿美, 谷地 一博, 高阪 真路, 三浪 友輔, 王 磊, 木村 太一, 谷野 美智枝, 西原 広史, 田中 伸哉, Brain Tumor Pathology, 34, Suppl., 093, 093, 2017年05月
日本脳腫瘍病理学会, 日本語 - グリオーマの日常診断におけるintegrated diagnosisの現状
谷野 美智枝, 谷川 聖, 石田 雄介, 木村 太一, 岡田 佳奈子, 佐藤 真実, 津田 真寿美, 西原 広史, 長嶋 和郎, 田中 伸哉, Brain Tumor Pathology, 34, Suppl., 102, 102, 2017年05月
日本脳腫瘍病理学会, 日本語 - RANKLによるインテグリンα2の発現亢進はインテグリンβ2の細胞内輸送を介して細胞接着を亢進する
大場雄介, 山田珠希, 山田珠希, 山田珠希, 津田真寿美, 藤岡容一朗, 藤岡真理, 堀内浩水, 堀口美香, 佐藤絢, ネパール ブラバ, 王せい, 柏木彩花, 西出真也, 南保明日香, 芳賀永, 田中伸哉, 進藤正信, 日本生理学雑誌(Web), 79, 2, 49 (WEB ONLY), 49, 2017年05月
(一社)日本生理学会, 日本語 - 髄膜腫におけるPOLR2A遺伝子変異の検討
鈴木 佑季, 津田 真寿美, 湯澤 明夏, 木村 太一, 石田 雄介, 谷野 美智枝, 西原 広史, 田中 伸哉, 日本病理学会会誌, 106, 1, 508, 508, 2017年03月
(一社)日本病理学会, 日本語 - 髄膜発生孤在性線維性腫瘍/血管周皮腫(SFT/HPC)におけるNAB2-STAT6融合遺伝子の解析
四宮 万里絵, 津田 真寿美, 湯澤 明夏, 木村 太一, 石田 雄介, 谷野 美智枝, 西原 広史, 田中 伸哉, 日本病理学会会誌, 106, 1, 508, 509, 2017年03月
(一社)日本病理学会, 日本語 - 浸潤性膀胱癌の転移および薬剤耐性獲得におけるAKR1C1の役割
津田 真寿美, 松本 隆児, 吉田 一彦, 谷野 美智枝, 木村 太一, 西原 広史, 阿部 崇重, 篠原 信雄, 野々村 克也, 田中 伸哉, 日本病理学会会誌, 106, 1, 340, 340, 2017年03月
(一社)日本病理学会, 日本語 - 合成ハイドロゲルが誘導する軟骨分化促進機序の解明
仙葉愼吾, 後藤佳子, 北村信人, 北村信人, 黒野定, 近江谷克裕, 津田真寿美, 津田真寿美, 黒川孝幸, 黒川孝幸, 田中伸哉, 田中伸哉, GONG Jian Ping, GONG Jian Ping, 安田和則, 再生医療, 16, 267, 2017年02月01日
日本語 - 前立腺癌診断におけるTripartite motif‐containing protein29(TRIM29)染色の有用性の検討
吉田一彦, 吉田一彦, 谷野美智枝, 堀井理絵, 木村太一, 津田真寿美, 近藤恒徳, 秋山太, 畠山鎮次, 田邉一成, 田中伸哉, 日本泌尿器科学会東部総会プログラム・抄録集, 82nd, 222, 2017年
日本語 - チロシンキナーゼ阻害剤耐性膠芽腫細胞における腫瘍幹細胞性獲得とSFRP1の関連性
鈴鹿 淳, 津田 真寿美, 王 磊, 谷野 美智枝, 木村 太一, 西原 広史, 田中 伸哉, 日本癌学会総会記事, 75回, J, 2036, 2016年10月
日本癌学会, 英語 - 肺癌においてアダプター蛋白CrkはTGF-βシグナルと協調してEMTを誘導する
谷野 美智枝, Elimansuri Aiman, Mahabir Roshan, 王 磊, 木村 太一, 西原 広史, 津田 真寿美, 田中 伸哉, 日本癌学会総会記事, 75回, P, 1092, 2016年10月
日本癌学会, 英語 - AKR1C1は膀胱癌の浸潤・転移と薬剤耐性を制御する
津田 真寿美, 松本 隆児, 吉田 一彦, 谷野 美智枝, 木村 太一, 西原 広史, 阿部 崇重, 篠原 信雄, 野々村 克也, 田中 伸哉, 日本癌学会総会記事, 75回, E, 1057, 2016年10月
日本癌学会, 英語 - 多形黄色星細胞腫におけるBRAFV600Eの遺伝子変異とリン酸化ERK及びp16の発現の検討
谷野 美智枝, 津田 真寿美, 石田 雄介, 木村 太一, 西原 広史, 長嶋 和郎, 田中 伸哉, 日本病理学会会誌, 105, 2, 75, 75, 2016年09月
(一社)日本病理学会, 日本語 - 脳腫瘍術中迅速病理診断における迅速免疫染色装置(ラピート)の使用経験
森谷 純, 谷野 美智枝, 木村 太一, 石田 雄介, 津田 真寿美, 西原 広史, 田中 伸哉, 日本病理学会会誌, 105, 2, 76, 76, 2016年09月
(一社)日本病理学会, 日本語 - Synthetic PAMPS gel functions as protein reservoir, which induces a chondrogenic differentiation of chondrocytic ATDC5 cells(和訳中)
仙葉 愼吾, 後藤 佳子, 北村 信人, 黒野 定, 近江谷 克裕, 津田 真寿美, 黒川 孝幸, グン・チェンピン, 田中 伸哉, 安田 和則, 日本生化学会大会プログラム・講演要旨集, 89回, [1T18, 05(1P, 2016年09月
(公社)日本生化学会, 英語 - 髄膜発生SFT/HPCのNAB2-STAT6融合遺伝子パターンと臨床病理学的検討
湯澤 明夏, 西原 広史, 王 磊, 津田 真寿美, 木村 太一, 谷野 美智枝, 田中 伸哉, Brain Tumor Pathology, 33, Suppl., 102, 102, 2016年05月
日本脳腫瘍病理学会, 日本語 - 臨床的シークエンス分析による髄膜腫の予後的影響(Prognostic impact for meningioma by clinical sequence system)
湯澤 明夏, 西原 広史, 山口 秀, 毛利 普美, 王 磊, 木村 太一, 津田 真寿美, 谷野 美智枝, 佐藤 典宏, 田中 伸哉, 日本病理学会会誌, 105, 1, 356, 356, 2016年04月
(一社)日本病理学会, 英語 - CRKアダプター蛋白質はHGF/c-Metフィードバックループを介して膀胱癌のEMTと転移を誘導する
王 磊, 松本 隆児, 津田 真寿美, 間石 奈湖, 安部 崇重, 木村 太一, 谷野 美智枝, 西原 広史, 樋田 京子, 大場 雄介, 篠原 信雄, 田中 伸哉, 日本癌学会総会記事, 74回, J, 1142, 2015年10月
日本癌学会, 英語 - 膀胱癌転移巣におけるAldo-keto reductase(AKR)1C1の発現亢進は浸潤能と抗癌剤耐性能を反映する
松本 隆児, 津田 真寿美, 安部 崇重, 篠原 信雄, 田中 伸哉, 野々村 克也, 日本泌尿器科学会総会, 103回, 471, 471, 2015年04月
(一社)日本泌尿器科学会総会事務局, 日本語 - 迅速免疫組織化学染色を用いた膠腫におけるIDH1染色の術中応用
廣嶋 優子, 南條 博, 前田 大地, 後藤 明輝, 笹嶋 寿郎, 清水 宏明, 南谷 佳弘, 津田 真寿美, 田中 伸哉, 日本病理学会会誌, 104, 1, 296, 296, 2015年03月
(一社)日本病理学会, 日本語 - トップランナーに聞く : 最先端の医療に挑む若手研究者への直撃インタビュー(49)がん治療抵抗性をもたらすシグナル伝達経路の解明と新規がん治療法・診断法の開発研究
津田 真寿美, 最新医学, 70, 2, 286, 292, 2015年02月
最新医学社, 日本語 - 胃低分化腺癌及び印環細胞癌におけるactionable mutationの網羅的検討
石川麻倫, 石川麻倫, 西原広史, 毛利普美, 毛利普美, 加藤容崇, WANG Lei, 木村太一, 津田真寿美, 谷野美智枝, 田中伸哉, 田中伸哉, 日本病理学会会誌, 104, 1, 2015年 - インフルエンザウイルスのCa2+シグナルを介した宿主細胞侵入機構
藤岡 容一朗, 津田 真寿美, 南保 明日香, 服部 ともえ, 佐々木 純子, 佐々木 雄彦, 宮崎 忠昭, 大場 雄介, 日本細胞生物学会大会講演要旨集, 66回, 103, 103, 2014年05月
(一社)日本細胞生物学会, 日本語 - インフルエンザウイルスのCa2+シグナルを介した宿主細胞侵入機構
藤岡 容一朗, 津田 真寿美, 南保 明日香, 服部 ともえ, 佐々木 純子, 佐々木 雄彦, 宮崎 忠昭, 大場 雄介, 日本細胞生物学会大会講演要旨集, 66回, 146, 146, 2014年05月
(一社)日本細胞生物学会, 日本語 - 大腸癌浸潤・転移におけるchorionic gonadotropin-βの機能解析とその臨床応用
川俣 太, 本間 重紀, 西原 広史, 長津 明久, 旭 よう, 蒲池 浩文, 高橋 典彦, 津田 真寿美, 田中 伸哉, 神山 俊哉, 武冨 紹信, 日本大腸肛門病学会雑誌, 67, 3, 240, 240, 2014年03月
(一社)日本大腸肛門病学会, 日本語 - Ras-PI3Kシグナルが制御する外来因子取込み機構の解析
藤岡 容一朗, 津田 真寿美, 服部 ともえ, 佐々木 純子, 佐々木 雄彦, 宮崎 忠昭, 大場 雄介, 日本生理学雑誌, 76, 2, 81, 81, 2014年03月
(一社)日本生理学会, 日本語 - The mesenchymal phenotype in recurrent glioblastoma is due to irradiation induced Snail expression and resultant EMT.
Roshan Mahabir, Mishie Tanino, Aiman Elmansuri, Masumi Tsuda, Taichi Kimura, Lei Wang, Hiroshi Nishihara, Shinya Tanaka, MOLECULAR CANCER THERAPEUTICS, 12, 11, 2013年11月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨(国際会議) - 消化器癌におけるERC/Mesothelinの分子病理学的検討(Molecular and clinicopathological analysis for ERC/Mesothelin in digestive cancers)
西原 広史, 川俣 太, 永生 高広, 津田 真寿美, 王 磊, 樋野 興夫, 武冨 紹信, 田中 伸哉, 日本癌学会総会記事, 72回, 308, 308, 2013年10月
日本癌学会, 英語 - Ras-PI3Kシグナルが制御する外来因子取込み機構の解析
藤岡 容一朗, 津田 真寿美, 服部 ともえ, 佐々木 純子, 佐々木 雄彦, 大場 雄介, 日本細胞生物学会大会講演要旨集, 65回, 153, 153, 2013年05月
(一社)日本細胞生物学会, 日本語 - SrcとAuroraキナーゼの2重阻害による滑膜肉腫の相乗的抗腫瘍効果
新井 隆太, 渡部 琢哉, 三浪 明男, 津田 真寿美, 大場 雄介, 北海道整形災害外科学会, 54, 2, 250, 2013年03月
日本語, 研究発表ペーパー・要旨(全国大会,その他学術会議) - 大腸癌浸潤・転移におけるchorionic gonadotropin‐βの機能解析とその臨床応用
川俣太, 本間重紀, 西原広史, 長津明久, 旭火華, 蒲池浩文, 高橋典彦, 津田真寿美, 田中伸哉, 神山俊哉, 武冨紹信, 日本消化器癌発生学会総会プログラム・抄録集, 24th, 85, 2013年
日本語 - 大腸癌浸潤・転移におけるchorionic gonadotropin‐βの機能解析とその臨床応用
川俣太, 本間重紀, 西原広史, 長津明久, 旭火華, 蒲池浩文, 高橋典彦, 津田真寿美, 田中伸哉, 神山俊哉, 武冨紹信, 大腸癌研究会プログラム・抄録集, 79th, 93, 2013年
日本語 - SU6656はSrcとオーロラキナーゼの二重阻害によってin vivo滑膜肉腫に対する有効な抗腫瘍効果を示す
新井 隆太, 渡部 琢哉, 津田 真寿美, 大場 雄介, 三浪 明男, 日本整形外科学会雑誌, 86, 8, S1101, 2012年08月
日本語, 研究発表ペーパー・要旨(全国大会,その他学術会議) - RANKLはインテグリンα2の発現とエンドサイトーシスを介したインテグリンの細胞内輸送を亢進する
我妻孝則, 津田真寿美, 山田珠希, 藤岡容一朗, 芳賀永, 戸塚靖則, 進藤正信, 大場雄介, 日本分子生物学会年会プログラム・要旨集(Web), 35th, 3P-0363 (WEB ONLY), 2012年
日本語 - SrcおよびAuroraキナーゼ2重阻害による滑膜肉腫の相乗的in vivo抗腫瘍効果(Dual inhibition of Src and Aurora kinases abrogates tumor growth, invasion, and angiogenesis of synovial sarcoma in vivo)
津田 真寿美, 新井 隆太, 渡部 琢哉, 尾瀬 農之, 小布施 力史, 前仲 勝実, 三浪 明男, 大場 雄介, 日本癌学会総会記事, 70回, 274, 274, 2011年09月
日本癌学会, 英語 - 慢性骨髄白血病に対する分子標的治療薬の反応性・抵抗性判定試験(Seeing response and resistance to BCR-ABL inhibition in chronic myeloid leukemia)
大場 雄介, 金安 顕子, 水谷 龍明, ダルマニン・ステファニー, 近藤 健, 津田 真寿美, 日本癌学会総会記事, 70回, 242, 242, 2011年09月
日本癌学会, 英語 - RANKLは口腔癌細胞のインテグリンα2の発現と細胞接着を亢進する(RANKL upregulates integrin α2 expression and cell adhesion in oral cancer cells)
大場 雄介, 山田 珠希, 藤岡 容一朗, 甲斐原 拓真, 戸塚 泰則, 進藤 正信, 津田 真寿美, 日本細胞生物学会大会講演要旨集, 63回, 156, 156, 2011年05月
(一社)日本細胞生物学会, 英語 - SU6656はAuroraキナーゼの阻害によってG2/M進行を阻止する
津田 真寿美, 新井 隆太, 大場 雄介, 日本細胞生物学会大会要旨集, 63rd, 159, 2011年05月
研究発表ペーパー・要旨(全国大会,その他学術会議) - 染色体・核・遺伝子発現・シグナル伝達 インフルエンザウイルスは、カルシウムシグナル伝達によって、Ras-PI3K-仲介エンドサイトーシスを活性化する(Signal transduction/Chromosome/Cell nucleus/Gene expression Influenza viruses activate Ras-PI3K-mediated endocytosis via calcium signaling)
藤岡 容一朗, 津田 真寿美, 服部 ともえ, 佐々木 純子, 佐々木 雄彦, 宮崎 忠昭, 大場 雄介, 日本細胞生物学会大会講演要旨集, 63回, 112, 112, 2011年05月
(一社)日本細胞生物学会, 英語 - SU6656はSrcとAuroraキナーゼの二重阻害によってヒト滑膜肉腫の進展を抑制する
新井 隆太, 津田 真寿美, 渡部 琢哉, 尾瀬 農之, 小布施 力史, 前仲 勝実, 三浪 明男, 大場 雄介, 日本分子生物学会年会プログラム・要旨集(Web), 34th, WEB ONLY 2P-0690, 2011年
研究発表ペーパー・要旨(全国大会,その他学術会議) - RANKL発現は腫瘍形成とEMTを亢進する(RANKL expression promotes tumorigenesis and epithelial mesenchymal transition)
山田 珠希, 津田 真寿美, 戸塚 靖則, 進藤 正信, 大場 雄介, 日本癌学会総会記事, 69回, 494, 494, 2010年08月
日本癌学会, 英語 - Srcファミリーキナーゼ阻害薬はin vivo滑膜肉腫の増殖・浸潤・血管新生を抑制する
新井 隆太, 渡部 琢哉, 津田 真寿美, 川口 秀明, 大場 雄介, 三浪 明男, 日本整形外科学会雑誌, 84, 8, S1244, 2010年08月
日本語, 研究発表ペーパー・要旨(全国大会,その他学術会議) - RANKLは微小環境特異的に発現し細胞接着・EMT・腫瘍形成を促進する生体内特異的機能マーカーである(RANKJL expression specifically observed in vivo promotes cell adhesion, epithelial mesenchymal transition, and tumor progression)
山田 珠希, 津田 真寿美, 進藤 正信, 戸塚 泰則, 大場 雄介, 日本細胞生物学会大会講演要旨集, 62回, 196, 196, 2010年05月
(一社)日本細胞生物学会, 英語 - メンブレントラフィック Ras-PI3Kシグナル経路がエンドサイトーシスとインフルエンザ感染を調節する(Membrane traffic The Ras-PI3K signaling pathway mediates endocytosis and the incorporation of influenza viruses)
藤岡 容一朗, 津田 真寿美, 服部 ともえ, 佐々木 純子, 佐々木 雄彦, 宮崎 忠昭, 大場 雄介, 日本細胞生物学会大会講演要旨集, 62回, 117, 117, 2010年05月
(一社)日本細胞生物学会, 英語 - 生体内腫瘍形成における腫瘍微小環境誘発性のRANKL発現の必要性(Requirement for tumor microenvironment-induced RANKL expression in the tumorigenesis in vivo)
山田 珠希, 津田 真寿美, 戸塚 靖則, 進藤 正信, 大場 雄介, 日本癌学会総会記事, 68回, 47, 47, 2009年08月
日本癌学会, 英語 - FRETバイオセンサーを用いたCML分子標的薬剤の薬効評価系の構築(A FRET-based biosensor for the evaluation of the efficacy of molecular targeted drugs for chronic myeloid leukemia)
水谷 龍明, 近藤 健, ダルマニン・ステファニー, 津田 真寿美, 田中 伸哉, 浅香 正博, 大場 雄介, 日本癌学会総会記事, 68回, 457, 457, 2009年08月
日本癌学会, 英語 - 悪性胸膜中皮腫におけるシグナル伝達アダプター分子CRKを介したRac活性の可視化
谷野美智枝, 王磊, 津田真寿美, 西原広史, 大場雄介, 矢野聖二, 曽根三郎, 田中伸哉, 日本呼吸器学会雑誌, 47, 237, 2009年05月10日
日本語, その他 - Receptor activator of NF‐kB ligand (RANKL)発現口腔癌細胞株の悪性形質に関する機能解析
山田珠希, 津田真寿美, 大場雄介, 川口秀明, 戸塚靖則, 進藤正信, 日本病理学会会誌, 98, 1, 250, 250, 2009年03月20日
(一社)日本病理学会, 日本語 - 慢性骨髄性白血病に対する分子標的治療薬の新たな薬効評価系の構築
水谷龍明, 近藤健, STEPHANIE Darmanin, 津田真寿美, 川口秀明, 浅香正博, 大場雄介, 日本病理学会会誌, 98, 1, 278, 2009年03月20日
日本語 - Involvement of Adaptor Protein Crk in Malignant Features of Human Mesothelioma.
M. A. Tanino, L. Wang, S. Kohsaka, T. Kimura, K. Sasai, H. Nishihara, M. Tsuda, S. Yano, S. Tanaka, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179, 2009年
AMER THORACIC SOC, 英語, 研究発表ペーパー・要旨(国際会議) - ヒト滑膜肉腫の増殖能と運動能に対するSrcファミリーキナーゼ阻害薬の効果
新井 隆太, 津田 真寿美, 渡部 琢哉, 川口 秀明, 大場雄介, 三浪 明男, 日本分子生物学会年会講演要旨集, 32nd, Vol.1, 231, 2009年
研究発表ペーパー・要旨(全国大会,その他学術会議) - Negative regulation of angiogenesis by zinc-finger transcription factor TCF8
Takayuki Inuzuka, Masumi Tsuda, Shinya Tanaka, Yujiro Higashi, Hideaki Kawaguchi, Yusuke Ohba, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 45, S11, S12, 2008年10月
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 英語, 研究発表ペーパー・要旨(国際会議) - 上皮細胞増殖因子(EGF)依存的なPTHrPの発現制御と口腔癌細胞の増殖能・局所浸潤能との関連性
山田珠希, 津田真寿美, 大場雄介, 川口秀明, 戸塚靖則, 進藤正信, 補体シンポジウム講演集, 45th, 180, 180, 2008年07月
(一社)日本補体学会, 日本語 - 口腔癌細胞における上皮細胞増殖因子受容体(EGFR)依存的なPTHrP発現制御と局所浸潤能との関連性
山田珠希, 津田真寿美, 大場雄介, 戸塚靖則, 進藤正信, 川口秀明, 適応医学, 12, 1, 25, 25, 2008年05月20日
日本適応医学会, 日本語 - Visualization of an interaction between Ras and Ras-binding domain in living cells by bimolecular fluorescence complementation
Kaori Tsutsumi, Masumi Tsuda, Hideaki Kawaguchi, Yusuke Ohba, FASEB JOURNAL, 22, 2008年04月
FEDERATION AMER SOC EXP BIOL, 英語, 研究発表ペーパー・要旨(国際会議) - 慢性骨髄性白血病に対する分子標的治療薬の新たな薬効評価系の構築
水谷龍明, 近藤健, DARMANIN Stephanie, 津田真寿美, 甲斐原拓真, 川口秀明, 浅香正博, 大場雄介, 生化学, 4P-1171, 2008年
日本語 - EGFシグナル伝達はPTHrPの発現を誘導し、口腔癌細胞の悪性化に関与する(EGF signaling regulates PTHrP expression and malignancies in oral cancer cells)
山田 珠希, 津田 真寿美, 大場 雄介, 戸塚 靖則, 進藤 正信, 日本癌学会総会記事, 66回, 501, 501, 2007年08月
日本癌学会, 英語 - シグナル伝達アダプター分子CrkによるERMの局在変化と細胞運動能及び接着能の解析
津田真寿美, 田中伸哉, 牧野吉倫, 西原広史, 沢洋文, 長嶋和郎, 日本癌学会総会記事, 61st, 317, 2002年08月25日
日本語, その他 - アダプター分子v‐CrkによるRho依存的細胞骨格制御と細胞運動能の解析
津田真寿美, 田中伸哉, 西原広史, 沢洋文, 長嶋和郎, 日本病理学会会誌, 91, 1, 159, 2002年02月28日
日本語, その他 - 滑膜肉腫の癌化機構におけるSYT‐SSX1キメラ蛋白の役割
長井真人, 田中伸哉, 平賀博明, 津田真寿美, 遠藤秀一, 沢洋文, 西原広史, 長嶋和郎, 日本病理学会会誌, 90, 1, 190, 2001年03月01日
日本語, その他 - ヒト滑膜肉腫関連蛋白SYT‐SSX1とクロマチンリモデリング因子hBRMの結合の機能解析
長井真人, 田中伸哉, 津田真寿美, 園部宏, 加藤宏幸, 平賀博明, 西原広史, 沢洋文, 長嶋和郎, 日本分子生物学会年会プログラム・講演要旨集, 23rd, 338, 2000年11月25日
日本語, その他 - ヒト滑膜肉腫関連SYT‐SSX1遺伝子の形質転換機構
長井真人, 田中伸哉, 沢洋文, 西原広史, 津田真寿美, 長嶋和郎, Jpn J Cancer Res, 91, Supplement (Sept), 53, 2000年09月01日
日本語, その他
講演・口頭発表等
- RANKLによるインテグリンα2の発現亢進はインテグリンβ2の細胞内輸送を介して細胞接着を亢進する
大場雄介, 山田珠希, 山田珠希, 山田珠希, 津田真寿美, 藤岡容一朗, 藤岡真理, 堀内浩水, 堀口美香, 佐藤絢, ネパール ブラバ, 王せい, 柏木彩花, 西出真也, 南保明日香, 芳賀永, 田中伸哉, 進藤正信
日本生理学雑誌(Web), 2017年05月, 日本語 - 浸潤性膀胱癌の転移および薬剤耐性獲得におけるAKR1C1の役割
津田真寿美, 松本隆児, 吉田一彦, 谷野美智枝, 木村太一, 西原広史, 阿部崇重, 篠原信雄, 野々村克也, 田中伸哉, 田中伸哉
日本病理学会会誌, 2017年03月24日, 日本語 - 髄膜発生孤在性線維性腫瘍/血管周皮腫(SFT/HPC)におけるNAB2‐STAT6融合遺伝子の解析
四宮万里絵, 津田真寿美, 湯澤明夏, 木村太一, 石田雄介, 谷野美智枝, 西原広史, 田中伸哉, 田中伸哉
日本病理学会会誌, 2017年03月24日, 日本語 - 髄膜腫におけるPOLR2A遺伝子変異の検討
鈴木佑季, 津田真寿美, 湯澤明夏, 木村太一, 石田雄介, 谷野美智枝, 西原広史, 田中伸哉, 田中伸哉
日本病理学会会誌, 2017年03月24日, 日本語 - 皮膚悪性黒色腫に対するオプジーボ(R)投与後に出現し免疫染色にてS‐100陰性を呈した転移性脳腫瘍の1例
石田雄介, 石田雄介, 石田雄介, 高橋達郎, 佐藤行真, 池田正起, 守田玲菜, 武井英博, 木村太一, 木村太一, 木村太一, 津田真寿美, 谷野美智枝, 田中伸哉, 田中伸哉
日本病理学会会誌, 2017年03月24日, 日本語 - 合成ハイドロゲルが誘導する軟骨分化促進機序の解明
仙葉愼吾, 後藤佳子, 北村信人, 北村信人, 黒野定, 近江谷克裕, 津田真寿美, 津田真寿美, 黒川孝幸, 黒川孝幸, 田中伸哉, 田中伸哉, GONG Jian Ping, GONG Jian Ping, 安田和則
再生医療, 2017年02月01日, 日本語 - ハイドロゲルを用いた癌幹細胞新規誘導法の開発
鈴鹿淳, 津田真寿美, 津田真寿美, 王磊, 王磊, 仙葉愼吾, 油谷幸代, 黒川孝幸, 近江谷克裕, 安田和則, 剣萍きょう, 田中伸哉, 田中伸哉
日本生化学会大会(Web), 2017年, 日本語 - 合成高分子ハイドロゲルによる癌幹細胞性誘導能の持続性の検討
石塚大暉, 津田真寿美, 津田真寿美, 王磊, 王磊, 鈴鹿淳, 安田和則, グン剣萍, 田中伸哉, 田中伸哉
日本生化学会大会(Web), 2017年, 日本語 - 前立腺癌診断におけるTripartite motif‐containing protein29(TRIM29)染色の有用性の検討
吉田一彦, 吉田一彦, 谷野美智枝, 堀井理絵, 木村太一, 津田真寿美, 近藤恒徳, 秋山太, 畠山鎮次, 田邉一成, 田中伸哉
日本泌尿器科学会東部総会プログラム・抄録集, 2017年, 日本語 - チロシンキナーゼ阻害剤耐性ヒト膠芽腫細胞におけるABCB4の機能解析
鍋島龍一, 津田真寿美, 津田真寿美, 鈴鹿淳, 王磊, 王磊, 谷野美智枝, 田中伸哉, 田中伸哉
日本生化学会大会(Web), 2017年, 日本語 - 機能性ハイドロゲルを用いた癌幹細胞性誘導に関する基礎的検討
青山佳代子, 津田真寿美, 津田真寿美, 王磊, 王磊, 鈴鹿淳, 安田和則, 剣萍きょう, 田中伸哉, 田中伸哉
日本生化学会大会(Web), 2017年, 日本語 - BRAF V600E変異検索およびKIAA1549‐BRAF融合遺伝子検索により診断に至った若年成人発症毛様細胞性星細胞腫
石田雄介, 津田真寿美, 澤村豊, 村井宏, 堀内成好, 長嶋和郎, 田中伸哉
日本病理学会会誌, 2016年09月30日, 日本語 - 脳腫瘍術中迅速病理診断における迅速免疫染色装置(ラピート)の使用経験
森谷純, 谷野美智枝, 木村太一, 石田雄介, 津田真寿美, 西原広史, 田中伸哉
日本病理学会会誌, 2016年09月30日, 日本語 - 多形黄色星細胞腫におけるBRAFV600Eの遺伝子変異とリン酸化ERK及びp16の発現の検討
谷野美智枝, 津田真寿美, 石田雄介, 木村太一, 西原広史, 長嶋和郎, 田中伸哉
日本病理学会会誌, 2016年09月30日, 日本語 - 血管内大細胞型B細胞性リンパ腫の剖検症例5例の浸潤性に関する病理組織学的検討
秋山采慧, 大森優子, 森谷純, 畑中佳奈子, 高阪真路, 木村太一, 津田真寿美, 西原広史, 谷野美智枝, 田中伸哉, 田中伸哉
日本病理学会会誌, 2016年04月12日, 日本語 - 大腸癌の異所性骨形成におけるBMP/Smadシグナルの作用とEMTとの関連性
上遠野なほ, 津田真寿美, 木村太一, 谷野美智枝, 西原広史, 田中伸哉, 田中伸哉
日本病理学会会誌, 2016年04月12日, 日本語 - 子宮頸癌細胞への放射線照射後の悪性転化におけるYAP1の役割の解析
岡森優唯, 谷野美智枝, 津田真寿美, 鈴鹿淳, 王磊, 森谷純, 木村太一, 石田雄介, 西原広史, 田中伸哉, 田中伸哉
日本分子生物学会年会プログラム・要旨集(Web), 2016年, 日本語 - チロシンキナーゼ阻害剤耐性ヒト膠芽腫細胞におけるABC transporterの同定
鍋島龍一, 津田真寿美, 鈴鹿淳, 王磊, 木村太一, 谷野美智枝, 田中伸哉, 田中伸哉
日本分子生物学会年会プログラム・要旨集(Web), 2016年, 日本語 - チロシンキナーゼ阻害剤耐性膠芽腫細胞における幹細胞性獲得とSFRP1の機能解析
鈴鹿淳, 津田真寿美, 王磊, 谷野美智枝, 木村太一, 西原広史, 田中伸哉, 田中伸哉
日本分子生物学会年会プログラム・要旨集(Web), 2016年, 日本語 - Pilomyxoid‐spectrum astrocytoma 2例の臨床病理学的検討―BRAF遺伝子異常の検討も加えて―
伊東民雄, 佐藤憲市, 及川光照, 杉尾啓徳, 浅野目卓, 尾崎義丸, 中村博彦, 田中伸哉, 津田真寿美, 長嶋和郎
Neurol Surg, 2015年09月10日, 日本語 - 複合糖質糖鎖を包括的に俯瞰する技術に立脚する細胞マーカーの探索
篠原康郎, 古川潤一, 津田真寿美, 岡田和恵, 木村太一, PIAO Jinhua, 田中伸哉
日本糖質学会年会要旨集, 2015年07月01日, 日本語 - 血管周皮腫・孤在性線維性腫瘍のFFPE検体を用いたNAB2‐STAT6融合遺伝子の検出
湯澤明夏, 西原広史, 加藤容崇, WANG Lei, 木村太一, 津田真寿美, 谷野美智枝, 田中伸哉
日本病理学会会誌, 2015年03月23日, 日本語 - 非小細胞肺癌(NSCLC)におけるHER2遺伝子変異の機能解析
中島穣太郎, 宮崎将也, 加藤容崇, WANG Lei, 木村太一, 津田真寿美, 谷野美智枝, 西原広史, 田中伸哉
日本病理学会会誌, 2015年03月23日, 日本語 - 胃低分化腺癌及び印環細胞癌におけるactionable mutationの網羅的検討
石川麻倫, 西原広史, 毛利普美, 加藤容崇, WANG Lei, 木村太一, 津田真寿美, 谷野美智枝, 田中伸哉
日本病理学会会誌, 2015年03月23日, 日本語 - 迅速免疫組織化学染色を用いた膠腫におけるIDH1染色の術中応用
廣嶋優子, 南條博, 前田大地, 後藤明輝, 笹嶋寿郎, 清水宏明, 南谷佳弘, 津田真寿美, 田中伸哉
日本病理学会会誌, 2015年03月23日, 日本語 - 次世代シークエンサーによる髄膜腫の遺伝子変異プロファイル解析
湯澤明夏, 西原広史, 毛利普美, 加藤容崇, 王磊, 木村太一, 木村太一, 津田真寿美, 谷野美智枝, 山口秀, 田中伸哉, 田中伸哉
Brain Tumor Pathol, 2015年, 日本語 - 糖鎖関連バイオマーカー探索を目的とした多段階脳腫瘍モデルの包括的な糖鎖解析
古川潤一, 津田真寿美, 岡田和恵, 木村太一, 朴錦花, 田中伸哉, 篠原康郎
日本生化学会大会(Web), 2015年, 日本語 - PAMPSゲルによるATDC5細胞のインスリン非依存性軟骨分化誘導シグナルの解明
後藤佳子, 北村信人, 和田進, 安田和則, 木村太一, 津田真寿美, 田中伸哉, 仙葉慎吾, 黒川孝幸, グン チェンピン
北海道整形災害外科学会, 2015年, 日本語 - 膠芽腫における分子標的阻害薬耐性獲得責任分子としてのIGFBP2の同定
津田真寿美, 王磊, 谷野美智枝, 木村太一, 西原広史, 田中伸哉, 田中伸哉
Brain Tumor Pathol, 2015年, 日本語 - 膀胱癌転移巣におけるAldo‐keto reductase(AKR)1C1の発現亢進は浸潤能と抗癌剤耐性能を反映する
松本隆児, 津田真寿美, 安部崇重, 篠原信雄, 田中伸哉, 野々村克也
日本泌尿器科学会総会プログラム抄録集(CD-ROM), 2015年, 日本語 - グリオーマモデル細胞を用いる不死化・癌化に伴う糖鎖発現変動の解析
篠原康郎, 津田真寿美, 古川潤一, 木村太一, 岡田和恵, PIAO Jinhua, 田中伸哉
日本糖質学会年会要旨集, 2014年07月23日, 日本語 - インフルエンザウイルスのCa2+シグナルを介した宿主細胞侵入機構
藤岡容一朗, 津田真寿美, 南保明日香, 服部ともえ, 佐々木純子, 佐々木雄彦, 宮崎忠昭, 宮崎忠昭, 大場雄介
日本細胞生物学会大会要旨集, 2014年05月15日, 日本語 - Ca2+シグナルを介したインフルエンザウイルス宿主細胞侵入メカニズムの解明
藤岡容一朗, 津田真寿美, 南保明日香, 服部ともえ, 佐々木純子, 佐々木雄彦, 宮崎忠昭, 大場雄介
日本分子生物学会年会プログラム・要旨集(Web), 2014年, 日本語 - miR‐17はp21を標的としヒト滑膜肉腫の細胞増殖能や腫瘍形成能を亢進させる
三浪友輔, 高阪真路, 谷地一博, 津田真寿美, 田中伸哉, 岩崎倫政
日本整形外科学会雑誌, 2013年08月30日, 日本語 - 新規シグナル特異的阻害剤スクリーニングシステムを用いた膠芽腫治療薬の探索
王磊, 津田真寿美, 菅野宏美, 木村太一, 谷野美智枝, 西原広史, 田中伸哉
日本病理学会会誌, 2013年04月26日, 日本語 - miR‐23aによる神経膠芽腫の浸潤能亢進とその機能解析
谷地一博, 高阪真路, 三浪友輔, 王磊, 木村太一, 谷野美智枝, 西原広史, 津田真寿美, 田中伸哉
日本病理学会会誌, 2013年04月26日, 日本語 - 軟部肉腫におけるシグナル伝達系の異常と治療への応用:滑膜肉腫をモデルにして
田中伸哉, 木村太一, 津田真寿美, 王磊, 仙葉慎吾, 谷野美智枝, 平賀博明, 大場雄介, 西原広史
日本病理学会会誌, 2013年04月26日, 日本語 - Ca2+シグナルを介したインフルエンザウイルスの宿主細胞侵入機構の解析
藤岡容一朗, 津田真寿美, 南保明日香, 服部ともえ, 佐々木純子, 佐々木雄彦, 宮崎忠昭, 大場雄介
日本分子生物学会年会プログラム・要旨集(Web), 2013年, 日本語 - 大腸癌浸潤・転移におけるchorionic gonadotropin‐βの機能解析とその臨床応用
川俣太, 本間重紀, 西原広史, 長津明久, 旭火華, 蒲池浩文, 高橋典彦, 津田真寿美, 田中伸哉, 神山俊哉, 武冨紹信
日本消化器癌発生学会総会プログラム・抄録集, 2013年, 日本語 - SU6656はSrcとオーロラキナーゼの二重阻害によってin vivo滑膜肉腫に対する有効な抗腫瘍効果を示す
新井隆太, 渡部琢哉, 津田真寿美, 大場雄介, 三浪明男
日本整形外科学会雑誌, 2012年08月25日, 日本語 - Ras‐PI3Kシグナルによる外来因子取込み制御機構の解析
藤岡容一朗, 津田真寿美, 服部ともえ, 佐々木純子, 佐々木雄彦, 宮崎忠昭, 宮崎忠昭, 大場雄介
日本分子生物学会年会プログラム・要旨集(Web), 2012年, 日本語 - RANKLはインテグリンα2の発現とエンドサイトーシスを介したインテグリンの細胞内輸送を亢進する
我妻孝則, 津田真寿美, 山田珠希, 山田珠希, 山田珠希, 藤岡容一朗, 芳賀永, 戸塚靖則, 進藤正信, 大場雄介
日本分子生物学会年会プログラム・要旨集(Web), 2012年, 日本語 - 慢性骨髄性白血病薬剤耐性細胞の分離と解析
金安顕子, 近藤健, DARMANIN Stephanie, DARMANIN Stephanie, 津田真寿美, 大場雄介
日本分子生物学会年会プログラム・要旨集(Web), 2011年, 日本語 - Srcファミリーキナーゼ阻害薬はin vivo滑膜肉腫の増殖・浸潤・血管新生を抑制する
新井隆太, 新井隆太, 渡部琢哉, 津田真寿美, 川口秀明, 大場雄介, 三浪明男
日本整形外科学会雑誌, 2010年08月25日, 日本語 - 悪性胸膜中皮腫におけるシグナル伝達アダプター分子CRKを介したRac活性の可視化
谷野美智枝, 王磊, 津田真寿美, 西原広史, 大場雄介, 矢野聖二, 曽根三郎, 田中伸哉
日本呼吸器学会雑誌, 2009年05月10日, 日本語 - 慢性骨髄性白血病に対する分子標的治療薬の新たな薬効評価系の構築
水谷龍明, 近藤健, STEPHANIE Darmanin, 津田真寿美, 川口秀明, 浅香正博, 大場雄介
日本病理学会会誌, 2009年03月20日, 日本語 - Receptor activator of NF‐kB ligand (RANKL)発現口腔癌細胞株の悪性形質に関する機能解析
山田珠希, 山田珠希, 山田珠希, 津田真寿美, 大場雄介, 川口秀明, 戸塚靖則, 進藤正信
日本病理学会会誌, 2009年03月20日, 日本語 - 上皮細胞増殖因子(EGF)依存的なPTHrPの発現制御と口腔癌細胞の増殖能・局所浸潤能との関連性
山田珠希, 山田珠希, 津田真寿美, 大場雄介, 川口秀明, 戸塚靖則, 進藤正信
補体シンポジウム講演集, 2008年07月, 日本語 - 口腔癌細胞における上皮細胞増殖因子受容体(EGFR)依存的なPTHrP発現制御と局所浸潤能との関連性
山田珠希, 山田珠希, 山田珠希, 津田真寿美, 大場雄介, 戸塚靖則, 進藤正信, 川口秀明
適応医学, 2008年05月20日, 日本語 - 慢性骨髄性白血病に対する分子標的治療薬の新たな薬効評価系の構築
水谷龍明, 近藤健, DARMANIN Stephanie, 津田真寿美, 甲斐原拓真, 川口秀明, 浅香正博, 大場雄介
生化学, 2008年, 日本語 - 上皮細胞増殖因子受容体阻害薬(EGFR‐TKI)による口腔癌細胞の顎骨浸潤抑制機構の検討
山口珠樹, 津田真寿美, 大場雄介, 樋田京子, 東野史裕, 戸塚靖則, 進藤正信
日本病理学会会誌, 2007年02月05日, 日本語 - 膜上へ移行したDock180のユビキチン化のこう進とElmo1による抑制。
牧野吉倫, 津田真寿美, 沢洋文, 沢洋文, 畠山鎮次, 田中伸哉, 長嶋和郎
日本分子生物学会年会講演要旨集, 2005年11月25日, 日本語 - bHLH型転写因子OLIG2による脳腫よう細胞増殖抑制機構の解明
たぶ康一, たぶ康一, 大西晶子, 沢洋文, 沢洋文, 津田真寿美, 酒井敏行, 田中伸哉, 長嶋和郎
日本癌学会学術総会記事, 2005年08月15日, 日本語 - ヒト滑膜肉腫細胞の癌化能におけるアダプター分子CRKの解析
渡部琢哉, 津田真寿美, 沢洋文, 三浪明男, 田中伸哉, 長嶋和郎
日本分子生物学会年会プログラム・講演要旨集, 2004年11月25日, 日本語 - グリア特異的転写因子OLIG2による脳腫よう細胞増殖抑制機構の解明
たぶ康一, 大西晶子, 寸田祐嗣, 鈴木忠樹, 津田真寿美, 酒井敏行, 沢洋文, 長嶋和郎
日本分子生物学会年会プログラム・講演要旨集, 2004年11月25日, 日本語 - 尿検体を用いたメチル化GSTP1プロモーター領域の検出による前立腺癌の診断法に関する検討
加藤智子, 津田真寿美, 沢洋文, 田中伸哉, 王らい, 市原真, 中田康信, 長嶋和郎
日本病理学会会誌, 2004年05月10日, 日本語 - JCウイルス核内移行機構の解析
沢洋文, QU Q, 鈴木忠樹, 仙葉慎吾, 逸見千寿香, 岡田由紀, 津田真寿美, 田中伸哉, 長嶋和郎
日本分子生物学会年会プログラム・講演要旨集, 2003年11月25日, 日本語 - ヒト滑膜肉腫癌遺伝子SYT‐SSXの細胞老化誘導能の解析
田中伸哉, 津田真寿美, 渡部琢哉, 木村太一, 小畑慶子, 沢洋文, 磯部健一, 赤城剛, 松田道行
日本分子生物学会年会プログラム・講演要旨集, 2003年11月25日, 日本語 - ヒト滑膜肉腫キメラ蛋白SYT‐SSX1による癌化及びp21依存的細胞増殖抑制機構の解明
津田真寿美, 田中伸哉, 渡部琢哉, 小畑慶子, 沢洋文, 長嶋和郎
日本癌学会総会記事, 2003年08月25日, 日本語 - シグナル伝達アダプター分子CrkによるERMの局在変化と細胞運動能及び接着能の解析
津田真寿美, 田中伸哉, 牧野吉倫, 西原広史, 沢洋文, 長嶋和郎
日本癌学会総会記事, 2002年08月25日, 日本語 - 滑膜肉腫の癌化機構におけるSYT‐SSX1キメラ蛋白の役割
長井真人, 田中伸哉, 平賀博明, 津田真寿美, 遠藤秀一, 沢洋文, 西原広史, 長嶋和郎
日本病理学会会誌, 2001年03月01日, 日本語 - ラット線維芽細胞におけるアダプター分子v‐Crkのアクチンストレスファイバー形成能の解析
津田真寿美, 田中伸哉, 沢洋文, 長嶋和郎
日本分子生物学会年会プログラム・講演要旨集, 2000年11月25日, 日本語 - ヒト滑膜肉腫関連蛋白SYT‐SSX1とクロマチンリモデリング因子hBRMの結合の機能解析
長井真人, 田中伸哉, 津田真寿美, 園部宏, 加藤宏幸, 平賀博明, 西原広史, 沢洋文, 長嶋和郎
日本分子生物学会年会プログラム・講演要旨集, 2000年11月25日, 日本語
共同研究・競争的資金等の研究課題
- 高機能ゲルによるゲノム制御:がん幹細胞リプログラミングの空間情報解析と治療薬開発
科学研究費助成事業
2024年04月01日 - 2029年03月31日
田中 伸哉, 津田 真寿美, 黒川 孝幸, 丸山 玲緒, 加藤 達哉
日本学術振興会, 基盤研究(S), 北海道大学, 24H00037 - 一軸配向化合成コラーゲン線維が誘導する骨髄幹細胞の分化と基質産生促進機序の解明
科学研究費助成事業
2022年04月01日 - 2025年03月31日
近藤 英司, 柚木 俊二, 津田 真寿美, 王 磊
日本学術振興会, 基盤研究(B), 北海道大学, 22H03918 - 新世代分子スイッチによるATPシステムの完全制御
科学研究費助成事業
2022年04月01日 - 2025年03月31日
玉置 信之, 津田 真寿美
日本学術振興会, 基盤研究(B), 北海道大学, 22H02153 - ハイドロゲルによるがん幹細胞誘導システムによる悪性中皮腫の幹細胞マーカーの同定
科学研究費助成事業
2021年04月01日 - 2024年03月31日
杉野 弘和, 津田 真寿美
悪性中皮腫は現在有効な治療法が確立されておらず、今後罹患者の増加が予測されているため、新規治療の開発が要求されている。北海道大学腫瘍病理学教室で開発されたハイドロゲル(DN gell: double network gell)を用いた迅速な癌幹細胞誘導技術(Nature Biomedical Engineering, 2021)により中皮腫幹細胞の性状解析、治療標的分子の同定を行うことを目的としている。
悪性中皮腫の細胞株(211H, H2052, H2452, Meso4, H28)をハイドロゲル上で培養すると、すべての細胞株で腫瘍細胞が集塊を形成した。一般的な幹細胞マーカーとして知られるSOX2、NANOG、OCT3/4のmRNAをqPCR法で調べると、NANOG、OCT3/4の発現増加が確認できた。これによりハイドロゲルによる癌幹細胞誘導技術は、悪性中皮腫の細胞株にも応用可能であることが示唆される。次にハイドロゲル上で培養した悪性中皮腫の細胞株(Meso4)の遺伝子発現プロファイルをマイクロアレイにより調べた。通常のpolystyrene dishやultra-low attachment surface dishで培養した比較対照群に対して、20倍以上の遺伝子発現増加を示す23遺伝子を同定した。細胞膜への局在が予測されている8遺伝子に着目して、qPCR法でも遺伝子発現の増加が確認できたのは4遺伝子であった。Meso4以外の細胞株(211H, H2052, H2452, H28)でも4遺伝子の発現をqPCR法で調べたところ、3遺伝子がMeso4と同様に発現増加を示した。この3遺伝子を悪性中皮腫の幹細胞マーカー候補遺伝子として解析を進める予定である。
日本学術振興会, 基盤研究(C), 国立研究開発法人国立がん研究センター, 21K08196 - 高強度ポーラスゲルによる3次元がん組織モデル創出とがん幹細胞標的新規治療法の開発
科学研究費助成事業
2021年04月01日 - 2024年03月31日
津田 真寿美, 野々山 貴行, 田中 伸哉
がんの再発は、がん治療に耐性を示すがん幹細胞が生き残ることによって起きる。がんの根絶には、がん組織におけるがん幹細胞の誕生・生存機構の解明が必須であるが、がん幹細胞が微量なことに加えて、従来のポリスチレンdish上でのがん細胞単独培養法は生体内のがん組織環境と大きく乖離しており、真の解明に至っていない。研究代表者らは、近年、高強度ダブルネットワークゲル(DNゲル)上にがん細胞を播種すると、24時間以内に迅速にがん幹細胞が誘導されるリプログラミング(初期化)現象を見出した(Nat. Biomed. Eng., 2021)。当該技術を基盤として、本研究ではがん組織におけるがん幹細胞の誕生・生存機序の解明を目指す。
令和3年度は、高頻度に再発を引き起こす肉腫の生体内環境を模倣するために、高強度DNゲルの作製技術と多孔質ゲルを得る凍結重合法を組み合わせて、高強度多孔質(ポーラス)ゲルを作製した。ポーラスゲルは、1st モノマーにアニオン性高分子NaAMPSを用い、2ndモノマーに中性高分子AAmを用いた。筋組織を模倣するため、細胞外基質としてフィブロネクチンを吸着後、GFPラベル筋芽細胞を播種し、細胞の接着や長期生存を検討した。AAmの濃度を変えることでポーラスサイズを調整し、さらに細胞の播種方法を改善することにより、ポーラスゲルの深部まで細胞が進展するよう3次元組織モデルを最適化した。このポーラスゲルをマウスの筋肉内に埋植すると、1週間以内に宿主細胞がゲル内に侵入して組織を復元した。一方、氷の成長方向を制御するフリーズキャスティング法を用いた凍結重合法により、筋組織を模倣した高度な配向構造を有するポーラスゲルの創製に成功した。
日本学術振興会, 基盤研究(B), 北海道大学, 21H03802 - 破骨細胞に発現する免疫チェックポイント分子シグレック-15の機能と治療応用
科学研究費助成事業
2021年04月01日 - 2024年03月31日
高畑 雅彦, 村上 正晃, 津田 真寿美
初年度は主に破骨細胞膜上のシグレック-15によるT細胞活性抑制効果の検証を中心におこなった。野生型マウス由来骨髄マクロファージから分化させたシグレック15を高発現する破骨細胞またはシグレック-15遺伝子欠損マウス由来骨髄マクロファージからII型コラーゲンコートディッシュ上で培養したシグレック15発現のない破骨細胞を用いてT-cellとの相互作用実験を行った。マウスシグレック-15発現破骨細胞または非発現破骨細胞と細胞透過性色素CFDA-SEで蛍光染色したCD4+T (Th1, Th17)、CD8+T細胞を共培養したところ、T細胞の細胞増殖性には明らかな差は生じなかったものの、シグレック-15発現破骨細胞はT-cellからのサイトカイン(IFNγ, IL-17, IL-22)分泌量を減少させることがわかった。
ヒト末梢血単球由来破骨細胞共培養系とヒトT-cellについても同様の実験を行い、破骨細胞由来のシグレック15はT細胞増殖性には明らかな変化を与えないが、T-cellからのサイトカイン分泌量を減少させ活性を抑制することを確認した。ヒト由来破骨細胞ではシグレック15遺伝子をノックダウンした細胞(単核破骨細胞)を用いた。
2年目の目標であるin vivoでの検証の準備として、転移性骨がんのモデルはマウス乳癌細胞株E0771およびルイス肺がん由来細胞株を免疫不全マウス、野生型マウスおよびシグレック15遺伝子欠損マウスに尾動脈経由で移植するモデルを作成中であり、免疫不全マウス以外ではモデルの最適化を行なっているところである。また、野生型マウスとシグレック15遺伝子欠損マウスを用いて、アジュバント誘導関節炎をモデルを作成中である。
日本学術振興会, 基盤研究(B), 北海道大学, 21H03048 - 高機能ゲルによるがん幹細胞リプログラミングと治療薬開発基盤の創出
科学研究費助成事業
2019年04月01日 - 2024年03月31日
田中 伸哉, 津田 真寿美, 高阪 真路, 黒川 孝幸, 前仲 勝実
(研究の骨格)本研究は、申請者が高機能ポリマーハイドロゲルを用いることで、極めて短時間にがん細胞のリプログラミングを誘導して、がん幹細胞を同定する方法見出したことにはじまる。これは従来のがん幹細胞分離同定法とは異なり、がんの種類を問わず24時間以内にがん幹細胞を同定することができる画期的な方法であり、本研究では、高機能ゲルのどのような物理学的因子ががん細胞の遺伝子発現変化を短時間で誘導するのかを検討し、高機能ゲルを基盤としたがん幹細胞診断法を開発し、さらにがん幹細胞標的治療薬を大規模スクリーニングにより創出するものである。(今年度の実績)「ゲル開発」プロジェクトでは、これまでの当該研究の結果から、陰性荷電を有するpoly-2-acrylamido- 2-methylpropanesulfonic acid (PAMPS) と中性荷電のpoly-N, N’- dimethylacrylamide (PDMAAm)にがん幹細胞誘導能が存在することが判明しており、とくにこれらのダブルネットワーク(DN)構造が重要であることが判明していた。さらに正と負の荷電両方有する両性荷電ゲルPCDME (poly-carboxymethyl -dimethyl-methacryloyloxy ethanaminium)もがん幹細胞誘導能を有することが判明していたが、当該年度の研究において負荷電を有するPNaSS(poly-sodium p-styrene sulfonate)のシングルネットワークゲルが、DNゲルより高いがん幹細胞誘導能を有することが明らかとなった。また、「臨床応用」のプロジェクトでは、従来検討されていなかった、ヒト肝臓がん(肝細胞がん)の細胞株を用いてDNゲルにより誘導した肝細胞がん幹細胞の解析から、ケモカイン受容体の1つであるCMKLR1が新規マーカーであることを発見した。
日本学術振興会, 基盤研究(A), 北海道大学, 19H01171 - 滑膜肉腫幹細胞の維持・制御に関わる遺伝子群の解析と新規治療法への応用
科学研究費助成事業
2020年04月01日 - 2023年03月31日
木村 太一, 津田 真寿美
本研究では先行研究により同定した滑膜肉腫幹細胞においてのみ特異的に発現上昇を呈する遺伝子、SS18-SSXに滑膜肉腫幹細胞特異的に結合するタンパクの解析とともに、滑膜肉腫幹細胞特異的SS18-SSX結合プロモーター領域の網羅的同定を行い、特にSWI/SNF型クロマチンリモデリング複合体と腫瘍幹細胞の性状、維持機構との関連を解析する事で新規治療法の創出を目指すものである。
cDNAマクロアレイを用いた網羅的な遺伝子発現比較解析によりCXCR4陽性の滑膜肉腫幹細胞及び幹細胞培養群で特異的に発現上昇する遺伝子とSS18-SSXにより腫瘍幹細胞中で発現制御される可能性のある15遺伝子を候補遺伝子とし研究を進めている。本年度は引き続き15遺伝子のうち滑膜肉腫幹細胞特異的に発現制御されている可能性が示唆された遺伝子から順にレンチウィルスベクターを用いたノックダウン細胞株を樹立し解析を行っている。
腫瘍幹細胞特異的なSS18-SSX結合タンパクの同定に関しては、質量分析計を用いた詳細な解析により幹細胞培養群でのみ結合することが示唆された15の候補タンパクの解析を進めている。大部分の候補タンパクは核内で転写調節にあずかるものであり、またそのうちの一つであるRBM14は実際にSS18-SSXとの結合が報告されていることから、結合実験の結果は概ね妥当と考えている。本年度は候補タンパクのうち文献上幹細胞性の制御にかかわる可能性が高いものについてレンチウィルスベクターを用いたノックダウン細胞株を樹立し解析を行っている。
腫瘍幹細胞特異的なSS18-SSX結合プロモーター領域の網羅的同定に関しては、引き続きChIPアッセイを施行する際の至適条件の検討を行ってきたが難航しており下記に示すような方針の変更を考えている。
日本学術振興会, 基盤研究(C), 北海道大学, 20K07441 - 癌の転移先臓器決定と覚醒におけるCrkおよびExosomeの機能解析
科学研究費助成事業
2018年04月01日 - 2021年03月31日
津田 真寿美, 田中 伸哉, 王 磊
本研究により、アダプター分子Crkはエクソソームの内包分子の種類と量を制御しており、Crk高発現膀胱癌細胞由来のエクソソームにはCrkとともにErbB2が含まれ、これが転移先臓器の肺の血管内皮細胞に作用し、膀胱癌細胞の肺転移を促進することが明らかになった。このことは、エクソソームに内包されているCrkやErbB2が転移先臓器のレシピエント細胞のシグナル伝達経路を活性化してその形質を変化させていることを示唆する。Crkを高発現しているがんは数多く報告されており、これによりエクソソームの内包分子についてもヘテロジェナイティーが創出され、がんの転移の選択と成立に寄与している可能性が示唆された。
日本学術振興会, 基盤研究(C), 北海道大学, 18K07059 - 滑膜肉腫における腫瘍幹細胞維持機構の解明と治療への応用
科学研究費助成事業
2016年04月01日 - 2019年03月31日
木村 太一, 津田 真寿美
cDNAマイクロアレイを用いた網羅的な遺伝子発現比較解析により滑膜肉腫幹細胞で特異的に発現上昇する遺伝子とSS18-SSXにより腫瘍幹細胞中で発現制御される可能性のある15遺伝子を候補遺伝子として抽出した。このうち滑膜肉腫幹細胞特異的に発現制御されている可能性の高い2遺伝子のノックダウン細胞株の樹立を行った。また腫瘍幹細胞特異的な15種のSS18-SSX結合タンパクを質量分析計を用いた詳細な解析により同定した。このうち文献上幹細胞性の制御にかかわる可能性が高い1つについてノックダウン細胞株を樹立したところ、幹細胞培養時にのみ細胞増殖が有意に低下することが明らかとなった。
日本学術振興会, 基盤研究(C), 北海道大学, 16K08703 - 多機能ゲルによる関節軟骨自然再生誘導法の最適化に関わる機序の解明と制御
科学研究費助成事業
2015年04月01日 - 2018年03月31日
北村 信人, グン 剣萍, 津田 真寿美, 黒川 孝幸, 仙葉 愼吾
軟骨基質高分子であるコンドロイチン硫酸(CS)、ヒアルロン酸(HA)を複合化したCS-DNゲル、HA-DNゲルを皮下および筋肉内に埋植し、その生体内劣化と組織適合性について検討した。埋植前の圧縮力学試験では、HA-DNゲルは破断強度7.90MPa、弾性率0.72MPaと従来のDNゲルより高い値を示し、CS-DNゲルの力学特性(破断強度2.47MPa、弾性率0.35MPa)より有意に高い値を示した(p<0.0001)。家兎10羽を用いた皮下埋植試験では、HA-DNゲルの力学特性は術後6週で有意に低下した(p<0.0001)。一方のCS-DNゲルは皮下埋植により力学特性の有意な変化は認めなかった。別の家兎21羽を用いた筋肉内埋植による生体内適合試験では、HA-DNゲルはほとんど炎症を生じなかったのに対し、CS-DNゲルは術後1週で陰性対照およびHA-DNゲルに対し有意に高い炎症を示した(p<0.0001、p=0.0043)。術後4週以降の炎症は陰性対照と同等となった。これらのDNゲル上でATDC5細胞を培養したところ、軟骨分化誘導因子(インスリン)の添加なしに、培養3日で2型コラーゲン、アグリカンの有意な発現上昇が認められた。これらの結果から、HA-DNゲル、CS-DNゲルは優れた生体適合性とともに軟骨分化誘導能を有することが明らかとなった。さらにこれら新規DNゲル上でATDC5細胞を培養しゲルが誘導する軟骨分化過程の細胞代謝を解析した。軟骨分化マーカーは培養早期より発現亢進が認められたが、ヒアルロン酸合成酵素やアポトーシス関連遺伝子には一定の挙動認められなかった。LC3、beclin1は培養12~24時間で対照に比べ高い発現を示し分化過程初期にオートファジー制御が関与していることが示唆された。
日本学術振興会, 基盤研究(B), 北海道大学, 15H03014 - PAMPSゲルが誘導する多様な細胞分化において共通する酵素発現動態と機序の解明
科学研究費助成事業
2013年04月01日 - 2016年03月31日
仙葉 愼吾, 安田 和則, 津田 真寿美, 津田 真寿美
PAMPSゲルは損傷軟骨の自然再生を誘導するがその機構は不明である。本研究では、ゲルに直接結合する細胞接着タンパク質としてインテグリンを同定した。また、軟骨原性細胞であるATDC5細胞をゲル上で培養すると、p38 MAPキナーゼの活性化状態が変化することを見いだした。さらに、PAMPSゲルは細胞外基質に関連した遺伝子発現を上昇させること、細胞外に分泌された細胞外基質がゲルに蓄積され、それらが軟骨分化を促進させることを明らかとした。以上の結果から、PAMPSゲルは細胞内シグナル分子を介して遺伝子発現を変化させるだけではなく、軟骨分化促進因子を蓄積するリザーバーとしても機能することが示唆された。
日本学術振興会, 基盤研究(C), 北海道大学, 25350548 - Crkアダプター分子を用いた幹細胞・EMTヘテロジェナイティーモデルの作製
科学研究費補助金(挑戦的萌芽研究)
2015年 - 2016年
津田真寿美
文部科学省, 研究代表者, 競争的資金 - 宿主細胞内シグナル伝達に着目したウイル感染対策基盤
科学研究費助成事業
2011年04月01日 - 2014年03月31日
大場 雄介, 津田 真寿美
ウイルス感染症は科学技術が進歩した現代でも人類最大の脅威の一つであり、2009年に世間を震撼させた新型インフルエンザパンデミックは記憶に新しい。我々はイメージングを用いたシグナル伝達研究の過程で、エンドゾームにおいてRasと結合したPI3Kが、エンドサイトーシス制御に重要な役割を担うことを明らかにした。本研究では、Ras-PI3Kシグナルがインフルエンザウイルス感染に重要なこと、また細胞内カルシウムがインフルエンザウイルス感染過程を制御するキーとなる分子であることを明らかにした。これらの成果の応用による宿主細胞因子を標的とする新概念のウイルス感染抑制法確立も期待される。
日本学術振興会, 基盤研究(B), 北海道大学, 23390090 - 次世代分子標的治療実現に向けたマルチキナーゼ阻害薬のリプロファイリング
科学研究費補助金(基盤研究(C))
2012年 - 2014年
津田 真寿美
現在、実臨床においてキナーゼを標的とした分子標的治療薬が使用されているが、耐性細胞の出現など克服すべき問題も多い。本研究では、各種分子標的治療薬に対する耐性メカニズムを解明し、耐性解除のために有効なキナーゼ阻害剤の選定とリプリファイリングを目的とした。本研究成果より、EGFR、c-Met、PDGFRに対する各種キナーゼ阻害剤耐性ヒト膠芽腫細胞株において、c-Met阻害剤はEGFRのATP結合部位に対する薬剤交叉は示さなかったものの、EGFR signalingを含めた複数のシグナル経路を抑制し、さらにPI3K阻害剤と併用することで薬剤耐性を解除できる可能性が示唆された。
文部科学省, 基盤研究(C), 北海道大学, 研究代表者, 競争的資金, 24590469 - 血管内皮細胞の内皮間葉移行による癌細胞の骨親和性獲得メカニズムの解明
科学研究費補助金(挑戦的萌芽研究)
2010年 - 2011年
津田 真寿美
近年増加傾向にある乳癌、前立腺癌、肺癌には、腫瘍発生後比較的早期から骨転移・骨浸潤が高頻度に出現する特徴がある。しかし、この原因は解剖学的位置関係だけでは説明困難であり、なぜこれらの癌が骨転移を起こしやすいのか未だ明らかではない。最近、腫瘍血管内皮細胞が内皮-間葉転換による脱分化の後、骨・軟骨細胞へ再分化して腫瘍組織の石灰化を誘導するという興味深い現象が報告された。これは、血管内皮細胞が作りだした骨類似環境によって、癌細胞が原発巣にいながらにしてすでに高骨親和性を獲得するようにプログラミングされる可能性を示唆している。当研究ではその可能性を検証するため、当該年度はまず、癌細胞と血管内皮細胞のどのような相互作用が腫瘍血管新生を惹起するのか、その詳細な分子メカニズムを解析した。臨床的に高頻度に骨転移を引き起こす滑膜肉腫では、腫瘍細胞がSrcファミリーキナーゼ(SFK)活性依存的に発現分泌するVEGFにより、血管内皮細胞が腫瘍組織へ積極的に導引されることが明らかとなった。SFK阻害剤をマウスの腹腔内へ投与した場合には、腫瘍血管新生が有意に抑制されると同時に、腫瘍の体積及び重量も著明に減少した。一方、高頻度に骨浸潤を引き起こす口腔癌では、癌細胞が分泌する破骨細胞分化因子RANKL依存的に血管内皮細胞が腫瘍組織へ導引されることが明らかとなった。このRANKLの発現はin vitro実験...
文部科学省, 挑戦的萌芽研究, 北海道大学, 研究代表者, 競争的資金, 22659078 - バイオイメージングによる上皮間葉・間葉上皮移行の分子基盤とダイナミクスの解明
科学研究費補助金(基盤研究(B))
2008年 - 2010年
大場 雄介, 津田 真寿美
がん細胞の浸潤・転移や血管内皮細胞の血管新生動員に重要なプロセスである上皮間葉移行(epithelial-mesenchymal transition, EMT)を共通に制御する転写因子TCF8を同定し、TCF8がEMTを制御する分子メカニズムをがん細胞側、血管内皮細胞側のそれぞれで解明した。また、がん間質側の違いが、がんそのものの悪性度に寄与する新たなエビデンスを見出し、新しいがんの制御法につながる新たな知見を提供した。
文部科学省, 基盤研究(B), 北海道大学, 連携研究者, 競争的資金, 20390107 - 新規開発ヒト腫瘍環境3次元モデルを用いた抗がん剤の最適適用診断
科学研究費補助金(若手研究(B))
2008年 - 2009年
津田 真寿美
生体内腫瘍環境特異的な癌細胞悪性化因子の解析を進める中で、口腔癌組織特異的に破骨細胞分化因子RANKLが発現誘導されることを同定し、このRANKLが生体内での口腔癌の悪性度を増悪させる重要因子である可能性を見出した。また、高頻度に肺転移を引き起こすヒト滑膜肉腫をモデルにして、腫瘍細胞と血管内皮細胞との相互作用が腫瘍血管新生に極めて重要であること、またSrcファミリー阻害薬がこの血管新生を有効に抑制することを明らかにした。
文部科学省, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 20790295 - 口腔がんの顎骨浸潤は抑制できるか?-EGFレセプターリン酸化阻害による効果-
科学研究費補助金(萌芽研究)
2007年 - 2008年
戸塚 靖則, 津田 真寿美, 進藤 正信, 大場 雄介, 北村 哲也, 樋田 京子, 東野 史裕
口腔がんの多くは舌や歯肉などの口腔内組織に発症するが、これらの臓器・組織は解剖学的に顎骨に近接しており、腫瘍の増大により容易に顎骨に浸潤する。この場合は、腫瘍の根治性の点から、顎骨離断術や部分切断術を施行せざるをえず、顔面の審美性や機能性に多大な障害を生じ、治癒後の社会生活やQOLに大きな影響を及ぼす。それ故、腫瘍の顎骨浸潤を抑制することが可能となれば、口腔がん患者にどって大きな福音となり、その開発が真に望まれている。口腔癌細胞の多くは、epidemal growth factor (EGF) receptorを高頻度に発現しており、また顎下腺並びに唾液中には高濃度のEGFが存在していることが明らかになっている。従って、口腔癌の微小環境中に存在するEGFが、癌細胞に対してパラクライン的に作用し、骨浸潤に関与する形質発現に重要な影響を及ぼしていることが示唆される。口腔がん細胞株HSC2, HSC3, HSC4, Ca9.22, SASを用いてEGFRの発現をWestern Blotで検討したところ、全てのがん細胞株でEGFRの発現亢進がみられた。これらの細胞をEGFで刺激した際、EGFRのリン酸化の亢進およびMAPKであるERK1/2, p38.JNKの活性化がみられた。ERK1/2はEGF依存的にPTHrPを発現亢進した。HSC2細胞にPTHrPのsiRNAを導入することで細...
文部科学省, 萌芽研究, 北海道大学, 連携研究者, 競争的資金, 19659515 - 染色体転座キメラ因子関連蛋白を標的とした抗がん剤の迅速適用と開発
科学研究費補助金(特別研究促進費, 若手研究(B))
2006年 - 2007年
津田 真寿美
染色体転座に由来する悪性腫瘍の多くは複雑な細胞動態を示し、一般的な化学療法に耐性で予後も悪いことから、より効果的な抗がん剤の適用やその診断が急務の課題となっている。我々は、平成18年度の研究より、キメラ遺伝子産物SYT-SSXを発現するヒト滑膜肉腫において、ある種のチロシンキナーゼ阻害剤がその増殖能や細胞運動能を著明に低下させることを明らかにした(特許出願:2007-3808)。この成果に基づき、当該年度においては、in vivoマウスにおけるチロシンキナーゼ阻害剤の抗腫瘍効果を検討した。ヌードマウスの皮下にヒト滑膜肉腫細胞株を接種して腫瘍塊を形成後、チロシンキナーゼ阻害剤を腹腔内投与し、腫瘍内のシグナル伝達抑制効果を経時的に解析した。この薬剤投与により、シグナル伝達経路のスウィチング分子として機能するGabl、さらには滑膜肉腫の増殖能に関与するp38 MAPKのリン酸化が著明に抑制されることが明らかとなった。この結果は、in vitroでの我々の解析結果と一致した。現在、この薬剤によるin vivoでの腫瘍抑制効果について更に検討中であり、臨床治験への可能性に向けて米国創薬会社と議論中である。更に、我々は染色体転座に由来する血液疾患である慢性骨髄性白血病(Chronic myelogenous leukemia;CML)において、蛍光共鳴エネルギー移動(Fluorescen...
文部科学省, 特別研究促進費, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 18799001
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特許権, 田中 伸哉, 津田 真寿美, 谷野 美智枝, 国立大学法人北海道大学
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特許権, 篠原 康郎, 田中 伸哉, 古川 潤一, 津田 真寿美, 国立大学法人北海道大学
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